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I decided to put a thread together reference inflammation/fibrosis.
DHT trigger an inflammation cascade which turn chronic.
DHT promotes VCAM-1 expression & activation of NF-KappaB. NF-Kappab is basically the on/off switch for chronic inflammation problems and diseases.
http://en.wikipedia.org/wiki/VCAM-1
The VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis and rheumatoid arthritis.
Upregulation of VCAM-1 in endothelial cells by cytokines occurs as a result of increased gene transcription (e.g., in response to Tumor necrosis factor-alpha (TNF-α) and Interleukin-1 (IL-1)) and through stabilization of Messenger RNA (mRNA) (e.g., Interleukin-4 (IL-4)). The promoter region of the VCAM-1 gene contains functional tandem NF-κB (nuclear factor-kappa B) sites. The sustained expression of VCAM-1 lasts over 24 hours.
http://en.wikipedia.org/wiki/NF-κB
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis[SUP][56][/SUP] and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases
Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappaB-dependent pathway.
Death AK, McGrath KC, Sader MA, Nakhla S, Jessup W, Handelsman DJ, Celermajer DS.
Author information
Abstract
There exists a striking gender difference in atherosclerotic vascular disease. For decades, estrogen was considered atheroprotective; however, an alternative is that androgen exposure in early life may predispose men to earlier atherosclerosis. We recently demonstrated that the potent androgen, dihydrotestosterone (DHT), enhanced the binding of monocytes to the endothelium, a key early event in atherosclerosis, via increased expression of vascular cell adhesion molecule-1 (VCAM-1). We now show that DHT mediates its effects on VCAM-1 expression at the promoter level through a novel androgen receptor (AR)/nuclear factor-kappaB (NF-kappaB) mechanism. Human umbilical vein endothelial cells were exposed to 4-400 nm DHT. DHT increased VCAM-1 mRNA in a dose- and time-dependent manner. The DHT effect could be blocked by the AR antagonist, hydroxyflutamide. DHT increased VCAM-1 promoter activity via NF-kappaB activation without affecting VCAM-1 mRNA stability. Using 5' deletion analysis, it was determined that the NF-kappaB sites within the VCAM-1 promoter region were responsible for the DHT-mediated increase in VCAM-1 expression; however, coimmunoprecipitation studies suggested there is no direct interaction between AR and NF-kappaB. Instead, DHT treatment decreased the level of the NF-kappaB inhibitory protein. DHT did not affect VCAM-1 protein expression and monocyte adhesion when female endothelial cells were tested. AR expression was higher in male, relative to female, endothelial cells, associated with increased VCAM-1 levels. These findings highlight a novel AR/NF-kappaB mediated mechanism for VCAM-1 expression and monocyte adhesion operating in male endothelial cells that may represent an important unrecognized mechanism for the male predisposition to atherosclerosis.
Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.
Author information
Abstract
Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-kappaB (NFkappaB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFkappaB activation in cerebral arteries and increased levels of the proinflammatory products of NFkappaB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFkappaB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This can be a reactive, benign, or pathological state. In response to injury this is called scarring and if fibrosis arises from a single cell line this is called a fibroma. Physiologically this acts to deposit connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing.[SUP][1][/SUP]
Fibrosis is similar to the process of scarring, in that both involve stimulated cells laying down connective tissue, including collagen and glycosaminoglycans. Immune cells called Macrophages, and damaged tissue between surfaces called interstitium release TGFbeta. This can be because of numerous reasons, including inflammation of the nearby tissue, or a generalised inflammatory state, with increased circulating mediators. TGFbeta stimulates the proliferation and activation of fibroblasts, which deposit connective tissue.[SUP][2]
[/SUP]
http://en.wikipedia.org/wiki/Fibrosis
Folliculitis is defined histologically as the presence of inflammatory cells within the wall and ostia of the hair follicle, creating a follicular-based pustule. The actual type of inflammatory cells can vary and may be dependent on the etiology of the folliculitis, the stage at which the biopsy specimen was obtained, or both. The inflammation can be either limited to the superficial aspect of the follicle with primary involvement of the infundibulum or the inflammation can affect both the superficial and deep aspect of the follicle. Deep folliculitis can eventuate from chronic lesions of superficial folliculitis or from lesions that are manipulated, and this may ultimately result in scarring.
Perifolliculitis, on the other hand, is defined as the presence of inflammatory cells in the perifollicular tissues and can involve the adjacent reticular dermis. Folliculitis and perifolliculitis can manifest independently or together as a result of follicular disruption and irritation.
This is a good evidence of chronic local inflammation.
Two 4 mm punch biopsies were performed on the occiput of the 7 controls and the wound was closed with 3-0 polyglactin 910.
Cosmet Dermatol. 2009 Jun;8(2):83-91
Androgenetic alopecia in males: a histopathological and ultrastructural study.
El-Domyati M, Attia S, Saleh F, Abdel-Wahab H.
Department of Dermatology, Faculty of Medicine, Al-Minya University, Al-Minya, Egypt.
Background Androgenetic alopecia is a common cosmetic hair disorder, resulting from interplay of genetic, endocrine, and aging factors leading to a patterned follicular miniaturization. Microinflammation seems to be a potential active player in this process. Aims To study the histopathological and ultrastructural changes occurring in male androgenetic alopecia (Androgenetic Alopecia). Patients/methods Fifty-five subjects were included in this study (40 with Androgenetic Alopecia and 15 as normal age-matched controls). Skin biopsies from frontal bald area and occipital hairy area were subjected to histopathological examination, immunohistochemical staining for collagen I and ultrastructural study. Results The frontal bald area of patients showed highly significant increase in telogen hairs and decrease in anagen/telogen ratio and terminal/vellus hair ratio (P < 0.001). Perifollicular inflammation was almost a constant feature in early cases and showed a significant correlation with perifollicular fibrosis (P = 0.048), which was more marked with thickening of the follicular sheath in advanced cases. Conclusion Follicular microinflammation plays an integral role in the pathogenesis of Androgenetic Alopecia in early cases. Over time, thickening of perifollicular sheath takes place due to increased deposition of collagen, resulting in marked perifollicular fibrosis, and sometimes ends by complete destruction of the affected follicles in advanced cases.
http://www.biomediclaser.com/pdf/Inf...c-Alopecia.pdf
Formation of fibrous tissue or fibroplasia of the dermal sheath, which surrounds the hair follicle, is now suspected to be a common terminal process resulting in the
miniaturization. Involution of the pilosebaceous unit in this form of baldness and sustained microscopic
follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is
considered a possible cofactor in the complex etiology of androgenetic alopecia. However, till date, the
inflammatory component has not been explored in developing treatment protocols for androgenetic
alopecia.
Fibrosing Alopecia in a Pattern DistributionPatterned Lichen Planopilaris or Androgenetic Alopecia With a Lichenoid Tissue Reaction Pattern?
Patients developed progressive fibrosing alopecia of the central scalp, without the multifocal areas of involvement typical of lichen planopilaris and pseudopelade. Perifollicular erythema, follicular keratosis, and loss of follicular orifices were limited to a patterned area of involvement. Biopsy specimens of early lesions demonstrated hair follicle miniaturization and a lichenoid inflammatory infiltrate targeting the upper follicle region. Advanced lesions showed perifollicular lamellar fibrosis and completely fibrosed follicular tracts indistinguishable from end-stage lichen planopilaris, pseudopelade, or follicular degeneration syndrome.
http://archderm.jamanetwork.com/article.aspx?articleid=189906
INFLAMMATORY PHENOMENA AND FIBROSIS
The implication of microscopic follicular inflammation in the pathogenesis of Androgenetic Alopecia has emerged from several independent studies: An early study referred to an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles, associated with an enlargement of the follicular dermal sheath composed of collagen bundles (perifollicular fibrosis), in regions of actively progressing alopecia.[25] Horizontal section studies of scalp biopsies indicated that the perifollicular fibrosis is generally mild, consisting of loose, concentric layers of collagen that must be distinguished from cicatricial alopecia.[26] The term 'microinflammation' has been proposed, because the process involves a slow, subtle, and indolent course, in contrast to the inflammatory and destructive process in the classical inflammatory scarring alopecias.[27] The significance of these findings has remained controversial. However, morphometric studies in patients with male pattern Androgenetic Alopecia treated with minoxidil showed that 55% of those with microinflammation had regrowth in response to treatment, in comparison to 77% in those patients without inflammation and fibrosis.[26] Moreover, some forms of primary fibrosing alopecia may represent pathological exaggeration of Androgenetic Alopecia associated with follicular inflammation and fibrosis, specifically postmenopausal frontal fibrosing alopecia,[28] and fibrosing alopecia in a pattern distribution.[29]
An important question is how the inflammatory reaction pattern is generated around the individual hair follicle. Inflammation is regarded as a multistep process which may start from a primary event. Some authors proposed that alopecia may result from cumulative physiological degeneration of selected hair follicles. They described in healthy murine skin clusters of perifollicular macrophages as perhaps indicating the existence of a physiological program of immunologically controlled hair follicle degeneration by which malfunctioning follicles are removed by programmed organ deletion, and suggested that perhaps an exaggerated form of this process might underlie some forms of primary scarring alopecia.[30] The observation of a perifollicular infiltrate in the upper follicle near the infundibulum of human hair follicles in Androgenetic Alopecia suggests that the primary causal event for the triggering of inflammation might occur near the infundibulum.[27] On the basis of this localization and the microbial colonization of the follicular infundibulum with Propionibacterium sp., Staphylococcus sp., Malassezia sp., or other members of the transient flora, one could speculate that microbial toxins or antigens could be involved in the generation of the inflammatory response. Alternatively, keratinocytes themselves may respond to oxidative stress from irritants, pollutants, and UV irradiation, by producing nitric oxide, and by releasing intracellularly stored IL-1α. This pro-inflammatory cytokine by itself has been shown to inhibit the growth of isolated hair follicles in culture. [31] Moreover, adjacent keratinocytes, which express receptors for IL-1, start to engage the transcription of IL-1 responsive genes: mRNA coding for IL-1β, TNFα, and IL-1α, and for specific chemokine genes, such as IL-8, and monocyte chemoattractant protein-1 (MCP-1) and MCP-3, themselves mediators for the recruitment of neutrophils and macrophages, have been shown to be upregulated in the epithelial compartment of the human hair follicle.[27] Besides, adjacent fibroblasts are also fully equipped to respond to such a pro-inflammatory signal. The upregulation of adhesion molecules for blood-borne cells in the capillary endothelia, together with the chemokine gradient, drives the transendothelial migration of inflammatory cells, which include neutrophils through the action of IL-8, T cells, and Langerhans cells at least in part through the action of MCP-1. After processing of localized antigen, Langerhans cells, or alternatively keratinocytes, which may also have antigen presenting capabilities, could then present antigen to newly infiltrating T lymphocytes and induce T-cell proliferation. The antigens are selectively destroyed by infiltrating macrophages, or natural killer cells. On the occasion that the causal agents persist, sustained inflammation is the result, together with connective tissue remodeling, where collagenases, such as matrix metalloproteinase (also transcriptionally driven by pro-inflammatory cytokines) play an active role.[27] Collagenases are suspected to contribute to the tissue changes in perifollicular fibrosis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929555/
Androgen Alopecia is a big cluster****.. and yeah the problem seems deeper that what most people think. Biopsies image vertical sectioning.
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Fibroplasia was noted, characterized by an increased number of fibroblasts and increased amounts of collagen around the sebaceous glands and collagenous streamers [ 9 ], in 62% of subjects (Figs. 4 , 5 and 6 ). .
http://www.springerimages.com/Images...3-003-0447-y-3
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Scalp pathology in androgenetic alopecia: horizontal section. Severe peri-isthmus and peri-sebaceous lymphocytic infiltrates with perifollicular fibrosis (HE ×60)
http://www.springerimages.com/Images...3-003-0447-y-7
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Scalp pathology in androgenetic alopecia: vertical section. Mild perifollicular fibrosis in the dermis (HE ×70)
http://www.springerimages.com/Images...3-003-0447-y-3
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http://openi.nlm.nih.gov/detailedres...108-g015&req=4
Androgenetic Alopecia is characterized by progressive miniaturization of hair follicles. When the biopsy specimen is sectioned transversely at the level of opening of sebaceous ducts into the hair follicle, the hairs shafts appear vastly different in diameter. The position of the original terminal follicle is indicated by a follicular streamer (stellae or fibrous tract) extending from the subcutaneous tissue up to the course of the follicle to the miniaturized hair. Decreased terminal hairs and increased follicular streamers therefore characterize Androgenetic Alopecia. Sebaceous glands seem enlarged in relation to the miniaturized hair follicles. There is significant reduction in total follicular counts, measured by horizontal sectioning of scalp biopsy. The progressive reduction in the duration of anagen causes a relative increase in telogen hair [Figures 13‐15].
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Some good links for more biopsies pictures..
http://www.dermpedia.org/dermpedia-textbook/androgenic-alopecia
http://www.dermaamin.com/site/histop...alopecia-.html
Really cool biopsies from healthy and Androgenic Alopecia scalps...click on the link for the pics..
https://www.inkling.com/read/mckees-...on-of-alopecia
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Histological features of peripilar signs associated with androgenetic alopecia.
Deloche C, de Lacharrière O, Misciali C, Piraccini BM, Vincenzi C, Bastien P, Tardy I, Bernard BA, Tosti A.
Source
Centre Charles Zviak, L'Oréal Recherche, 90 rue du Général Roguet, 92583 Clichy Cedex, France.
Abstract
BACKGROUND:
A study of the scalp in a large cohort of volunteers with androgenetic alopecia using macrophotographs showed the presence of peripilar signs (PPS) around the hair ostia.
OBJECTIVE:
The aim of the present study was to establish the histopathological features related to PPS.
DESIGN:
Prospective clinicopathological study. SETTING. Department of Dermatology, University Hospital of Bologna.
PATIENTS:
A group of 40 patients (21 males and 19 females) participated in the study. Macrophotographs of the scalp were taken using a Dermaphot camera and PPS were scored using a three-point scale. Hair density and PPS were clinically scored according to reference scales. Two punch biopsies from the photographed area were obtained from each subject and histological analysis was performed on vertical and horizontal sections.
OBSERVATIONS:
Clinical parameters indicated that PPS were already detectable on scalp with high hair density. Moreover, in patients with high hair density (score >4), a significant relationship was found between the PPS score and the global score for perifollicular infiltrates. Thus PPS are linked to superficial perifollicular lymphocytic infiltrates in early androgenetic alopecia.
CONCLUSIONS:
PPS could be the clinical signs reflecting the presence of perifollicular infiltrates.
Scalp dermoscopy of androgenetic alopecia in Asian people.
Inui S, Nakajima T, Itami S.
Source
Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Abstract
Although dermoscopy is used mainly for diagnosing pigmented skin lesions, this device has been reported to be useful in observing alopecia areata and frontal fibrosing alopecia. Herein, we investigated the dermoscopic features and their incidence of androgenetic alopecia (Androgenetic Alopecia; n = 50 men) and female Androgenetic Alopecia (***A; n = 10 women) in Asian people. More than 20% hair diameter diversity (HDD), which reportedly is an early sign of Androgenetic Alopecia and corresponds to hair follicle miniaturization, was observed in the affected area of all Androgenetic Alopecia and ***A cases, suggesting that HDD is an essential feature to diagnose Androgenetic Alopecia and ***A. Peripilar signs, corresponding to perifollicular pigmentation, were seen in 66% (33/50) of Androgenetic Alopecia and 20% (2/10) of ***A women. This incidence in the present study was lower than previously reported in white subjects possibly because the Asian skin color conceals slight peripilar pigmentation. Yellow dots were observed in 26% (13/50) of Androgenetic Alopecia and 10% (1/10) of ***A cases and the number of yellow dots in Androgenetic Alopecia and ***A was limited to 10 on the overall hair loss area. Yellow dots possibly indicate the coincidence of Androgenetic Alopecia and enlargement of the sebaceous glands caused by common end-organ hypersensitivity to androgen. In conclusion, dermoscopy is useful to diagnose Androgenetic Alopecia and ***A and provides insights into the pathogenesis of Androgenetic Alopecia.
“During the hair cycle the follicle has to be rebuilt from stem cells,” explains Dr Bruno Bernard, director of research for life sciences at L’Oreal. “Stem cells in human hair follicles are localised in two different reservoirs – one is in the upper part of the follicle and the other in the lower part.
“The cells in the lower part are required to activate the cells in the upper part and so help to maintain the follicle function. The thickening of collagen in the connective tissue sheath, which sits around the base of the hair follicle, prevents the movement of stem cells from the lower reservoir to the upper reservoir. Bit by bit, the follicle is squeezed and causes the follicles to grow smaller and smaller.” Indeed, research from The Rockefeller University in New York suggests movement between the two groups of stem cells is crucial in normal hair growth.
http://www.telegraph.co.uk/science/8...he-corner.html
. [SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1]Perifollicular sheath is the major problem in Androgen Alopecia.[/SIZE][/SIZE][/SIZE][/SIZE][/SIZE]
[SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1] http://dopingjournal.org/content/5/3/[/SIZE][/SIZE][/SIZE][/SIZE][/SIZE]
Male pattern alopecia a histopathologic and histochemical study.
Lattanand A, Johnson WC.
Abstract
Three hundred and forty-seven tissue specimens were studied from 23 patients with male pattern alopecia. Characteristic features of pattern alopecia included: the presence of miniature or vellus follicles; a marked enlargement of the sebaceous glands and arrectores pilorum muscles; the presence of connective tissue streamers beneath the vellus follicles; and the thinning of the dermis. A mild perivascular infiltrate of mononuclear cells and mild capillary dilatation was sometimes seen. An increased number of mast cells was often a prominent feature. Histochemical procedures were performed for glycogen, acid mucosaccharides, inorganic substances, and enzymes including alkaline phosphatase, acid phosphatase, beta glucuronidase, cholinesterase, aminopeptidase, oxidases and dehydrogenases. Histochemical studies did not reveal any significantly abnormal enzyme changes other than the altered vascular and nerve supply to the the miniature follicles.
J Drugs Dermatol. 2011 Dec;10(12):1404-11.
The role of inflammation and immunity in the pathogenesis of androgenetic alopecia.
Magro CM, Rossi A, Poe J, Manhas-Bhutani S, Sadick N.
Author information
Abstract
BACKGROUND:
Female pattern hair loss affects many women; its pathogenetic basis has been held to be similar to men with common baldness.
OBJECTIVE:
The objective of this study was to determine the role of immunity and inflammation in androgenetic alopecia in women and modulate therapy according to inflammatory and immunoreactant profiles.
MATERIALS AND METHODS:
52 women with androgenetic alopecia (AA) underwent scalp biopsies for routine light microscopic assessment and direct immunofluroescent studies. In 18 patients, serologic assessment for antibodies to androgen receptor, estrogen receptor and cytokeratin 15 was conducted.
RESULTS:
A lymphocytic folliculitis targeting the bulge epithelium was observed in many cases. Thirty-three of 52 female patients had significant deposits of IgM within the epidermal basement membrane zone typically accompanied by components of complement activation. The severity of changes light microscopically were more apparent in the positive immunoreactant group. Biopsies from men with androgenetic alopecia showed a similar pattern of inflammation and immunoreactant deposition. Serologic assessment for antibodies to androgen receptor, estrogen receptor or cytokeratin 15 were negative. Combined modality therapy with minocycline and topical steroids along with red light produced consistent good results in the positive immunoreactant group compared to the negative immunoreactant group.
CONCLUSION:
A lymphocytic microfolliculitis targeting the bulge epithelium along with deposits of epithelial basement membrane zone immunoreactants are frequent findings in androgenetic alopecia and could point toward an immunologically driven trigger. Cases showing a positive immunoreactant profile respond well to combined modality therapy compared to those with a negative result.
Acute Inflammation ( Induced by the derma roller)
Acute inflammation is a normal process that protects and heals the body following physical injury or infection. Acute inflammation involves local dilation of blood vessels as well as increased vessel permeability to improve blood flow to the injured area. At the site of an infection or injury, mast cells, platelets, nerve endings, endothelial cells, and other resident cells release signaling molecules and chemoattractants that recruit leukocytes to the affected area. Neutrophils, a type of granulocyte, are the first leukocytes to appear at the injured site. These cells phagocytose (engulf) and kill invading microorganisms through the release of non-specific toxins, such as superoxide radicals, hypochlorite, and hydroxyl radicals; these reactive oxygen species (ROS) kill pathogens as well as adjacent cells, sick and healthy alike. Neutrophils also release cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, gamma interferon (INF-gamma), and others. Such pro-inflammatory cytokines in turn induce the liver to synthesize various acute phase reactant proteins and also induce systemic inflammatory responses (e.g., fever and leukocytosis—a rise in the number of white blood cells). Neutrophils are short-lived and are thus primarily involved in the early stages of inflammation.
Hemostasis:
Once the source of damage to a house has been removed and before work can start, utility workers must come in and cap damaged gas or water lines. So too in wound healing damaged blood vessels must be sealed. In wound healing the platelet is the cell which acts as the utility worker sealing off the damaged blood vessels. The blood vessels themselves constrict in response to injury but this spasm ultimately relaxes. The platelets secrete vasoconstrictive substances to aid in this process but their prime role is to form a stable clot sealing the damaged vessel. Under the influence of ADP (adenosine diphosphate) leaking from damaged tissues the platelets aggregate and adhere to the exposed collagen. They also secrete factors which interact with and stimulate the intrinsic clotting cascade through the production of thrombin, which in turn initiates the formation of fibrin from fibrinogen. The fibrin mesh strengthens the platelet aggregate into a stable hemostatic plug. Finally platelets also secrete cytokines such as platelet-derived growth factor (PDGF), which is recognized as one of the first factors secreted in initiating subsequent steps. Hemostasis occurs within minutes of the initial injury unless there are underlying clotting disorders.
Inflammation Phase:
Clinically inflammation, the second stage of wound healing presents as erythema, swelling and warmth often associated with pain, the classic “rubor et tumor c*m calore et dolore”. This stage usually lasts up to 4 days post injury. In the wound healing analogy the first job to be done once the utilities are capped is to clean up the debris. This is a job for non-skilled laborers. These non-skilled laborers in a wound are the neutrophils or PMN’s (polymorphonucleocytes). The inflammatory response causes the blood vessels to become leaky releasing plasma and PMN’s into the surrounding tissue. The neutrophils phagocytize debris and microorganisms and provide the first line of defense against infection. They are aided by local mast cells. As fibrin is broken down as part of this clean-up the degradation products attract the next cell involved. The task of rebuilding a house is complex and requires someone to direct this activity or a contractor. The cell which acts as “contractor” in wound healing is the macrophage. Macrophages are able to phagocytize bacteria and provide a second line of defense. They also secrete a variety of chemotactic and growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-__ and interleukin-1 (IL-1) which appears to direct the next stage.
Proliferative Phase ( Proliferation, Granulation and Contraction):
The granulation stage starts approximately four days after wounding and usually lasts until day 21 in acute wounds depending on the size of the wound. It is characterized clinically by the presence of pebbled red tissue in the wound base and involves replacement of dermal tissues and sometimes subdermal tissues in deeper wounds as well as contraction of the wound. In the wound healing analogy once the site has been cleared of debris, under the direction of the contractor, the framers move in to build the framework of the new house. Sub-contractors can now install new plumbing and wiring on the framework and siders and roofers can finish the exterior of the house. The “framer” cells are the fibroblasts which secrete the collagen framework on which further dermal regeneration occurs. Specialized fibroblasts are responsible for wound contraction. The “plumber” cells are the pericytes which regenerate the outer layers of capillaries and the endothelial cells which produce the lining. This process is called angiogenesis. The “roofer” and “sider” cells are the keratinocytes which are responsible for epithelialization. In the final stage of epithelializtion, contracture occurs as the keratinocytes differentiate to form the protective outer layer or stratum corneum.
Remodeling or Maturation Phase:
Once the basic structure of the house is completed interior finishing may begin. So too in wound repair the healing process involves remodeling the dermal tissues to produce greater tensile strength. The principle cell involved in this process is the fibroblast. Remodeling can take up to 2 years after wounding and explains why apparently healed wounds can break down so dramatically and quickly if attention is not paid to the initial causative factors.
Chronic Inflammation ( Androgen Alopecia)
If the stimulus persists, inflammation can last days, months, and even years. Chronic inflammation is primarily mediated by monocytes and long-lived macrophages; monocytes mature into macrophages once they leave the bloodstream and enter tissues. Macrophages engulf and digest microorganisms, foreign invaders, and senescent cells. Macrophages release several different chemical mediators, including IL-1, TNF-alpha, and prostaglandins, that perpetuate the pro-inflammatory response. At later stages, other cells, including lymphocytes, invade the affected tissues: T lymphocytes kill virus-infected cells and B lymphocytes produce antibodies that specifically target the invading microorganisms for destruction.
Macrophages and other leukocytes release ROS and proteases that destroy the source of inflammation; however, damage to the body's own tissues often results. In fact, tissue damage is a hallmark of chronic inflammation. Another characteristic of chronic inflammation is repair of the damaged tissue by replacement with cells of the same type or with fibrous connective tissue. An important part of the inflammatory process involves local angiogenesis—the development of new blood vessels. In some instances, the body is unable to repair tissue damage, and the inflammatory cascade continues. Chronic inflammation is abnormal and does not benefit the body; in fact, chronic inflammation is involved in a number of disease states.
http://www.vetmed.vt.edu/education/...thology/INFLAMMATION LAB/INFLAMMATION LAB.htm
Prostaglandin D[SUB]2[/SUB] Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/
Markers and Mediators of Inflammation
Nuclear factor kappa-B (NF-kB) is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-kB, which turns on the expression of over 400 genes involved in the inflammatory response (Sethi et al. 2008). These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex®).
http://en.wikipedia.org/wiki/NF-κB
Tumor necrosis factor alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells) (Green et al. 1976), TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types (Sethi et al. 2008). Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion (Kundu et al. 2008).
http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha
Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.
http://en.wikipedia.org/wiki/Interleukin
C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells (Meyer 2010). CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections (Windgassen et al. 2011). Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke (Emerging Risk Factors Collaboration et al. 2010).
http://en.wikipedia.org/wiki/C-reactive_protein
Eicosanoids. The cytokine factors mentioned above (interleukins, TNF-α) are “long-distance messages”. They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses (Luo et al. 2011). There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.
Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes (see below) (Serhan et al. 2001).
http://en.wikipedia.org/wiki/Eicosanoid
Cyclooxygenases and Lipoxygenases. The eicosanoids (above) require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and the non-steroidal anti- inflammatory drugs (NSAIDS, like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process: it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.
http://en.wikipedia.org/wiki/Cyclooxygenase
Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response (Luo et al. 2011). Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy
While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins), The proper transition from the pro- to anti-inflammatory activities of the COX and LOX enzymes is an important for the progression of a healthy inflammatory response.
http://en.wikipedia.org/wiki/Lipoxygenase
DHT trigger an inflammation cascade which turn chronic.
DHT promotes VCAM-1 expression & activation of NF-KappaB. NF-Kappab is basically the on/off switch for chronic inflammation problems and diseases.
http://en.wikipedia.org/wiki/VCAM-1
The VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium. It also functions in leukocyte-endothelial cell signal transduction, and it may play a role in the development of atherosclerosis and rheumatoid arthritis.
Upregulation of VCAM-1 in endothelial cells by cytokines occurs as a result of increased gene transcription (e.g., in response to Tumor necrosis factor-alpha (TNF-α) and Interleukin-1 (IL-1)) and through stabilization of Messenger RNA (mRNA) (e.g., Interleukin-4 (IL-4)). The promoter region of the VCAM-1 gene contains functional tandem NF-κB (nuclear factor-kappa B) sites. The sustained expression of VCAM-1 lasts over 24 hours.
http://en.wikipedia.org/wiki/NF-κB
Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, atherosclerosis[SUP][56][/SUP] and others. It is important to note though, that elevation of some NF-κB inhibitors, such as osteoprotegerin (OPG), are associated with elevated mortality, especially from cardiovascular diseases
Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappaB-dependent pathway.
Death AK, McGrath KC, Sader MA, Nakhla S, Jessup W, Handelsman DJ, Celermajer DS.
Author information
Abstract
There exists a striking gender difference in atherosclerotic vascular disease. For decades, estrogen was considered atheroprotective; however, an alternative is that androgen exposure in early life may predispose men to earlier atherosclerosis. We recently demonstrated that the potent androgen, dihydrotestosterone (DHT), enhanced the binding of monocytes to the endothelium, a key early event in atherosclerosis, via increased expression of vascular cell adhesion molecule-1 (VCAM-1). We now show that DHT mediates its effects on VCAM-1 expression at the promoter level through a novel androgen receptor (AR)/nuclear factor-kappaB (NF-kappaB) mechanism. Human umbilical vein endothelial cells were exposed to 4-400 nm DHT. DHT increased VCAM-1 mRNA in a dose- and time-dependent manner. The DHT effect could be blocked by the AR antagonist, hydroxyflutamide. DHT increased VCAM-1 promoter activity via NF-kappaB activation without affecting VCAM-1 mRNA stability. Using 5' deletion analysis, it was determined that the NF-kappaB sites within the VCAM-1 promoter region were responsible for the DHT-mediated increase in VCAM-1 expression; however, coimmunoprecipitation studies suggested there is no direct interaction between AR and NF-kappaB. Instead, DHT treatment decreased the level of the NF-kappaB inhibitory protein. DHT did not affect VCAM-1 protein expression and monocyte adhesion when female endothelial cells were tested. AR expression was higher in male, relative to female, endothelial cells, associated with increased VCAM-1 levels. These findings highlight a novel AR/NF-kappaB mediated mechanism for VCAM-1 expression and monocyte adhesion operating in male endothelial cells that may represent an important unrecognized mechanism for the male predisposition to atherosclerosis.
Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.
Author information
Abstract
Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-kappaB (NFkappaB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFkappaB activation in cerebral arteries and increased levels of the proinflammatory products of NFkappaB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFkappaB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This can be a reactive, benign, or pathological state. In response to injury this is called scarring and if fibrosis arises from a single cell line this is called a fibroma. Physiologically this acts to deposit connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing.[SUP][1][/SUP]
Fibrosis is similar to the process of scarring, in that both involve stimulated cells laying down connective tissue, including collagen and glycosaminoglycans. Immune cells called Macrophages, and damaged tissue between surfaces called interstitium release TGFbeta. This can be because of numerous reasons, including inflammation of the nearby tissue, or a generalised inflammatory state, with increased circulating mediators. TGFbeta stimulates the proliferation and activation of fibroblasts, which deposit connective tissue.[SUP][2]
[/SUP]
http://en.wikipedia.org/wiki/Fibrosis
Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis
Satoshi Ueha[SUP]1,2[/SUP], Francis H. W. Shand[SUP]1,3[/SUP] and Kouji Matsushima[SUP]1,2[/SUP]*
Organ fibrosis is a pathological condition associated with chronic inflammatory diseases. In fibrosis, excessive deposition of extracellular matrix (ECM) severely impairs tissue architecture and function, eventually resulting in organ failure. This process is mediated primarily by the induction of myofibroblasts, which produce large amounts of collagen I, the main component of the ECM. Accordingly, the origin, developmental pathways, and mechanisms of myofibroblast regulation are attracting increasing attention as potential therapeutic targets. The fibrotic cascade, from initial epithelial damage to eventual myofibroblast induction, is mediated by complex biological processes such as macrophage infiltration, a shift from Th1 to Th2 phenotype, and by inflammatory mediators such as transforming growth factor-β. Here, we review the current understanding of the cellular and molecular mechanisms underlying organ fibrosis.
http://www.frontiersin.org/Journal/1...00071/abstract
Satoshi Ueha[SUP]1,2[/SUP], Francis H. W. Shand[SUP]1,3[/SUP] and Kouji Matsushima[SUP]1,2[/SUP]*
- [SUP]1[/SUP] Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- [SUP]2[/SUP] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan
- [SUP]3[/SUP] Departmhttp://www.hairlosstalk.com/interact/showthread.php/69374-New-Dermaroller-Study-Thoughts-comments/page386ent of Pharmacology, University of Melbourne, Melbourne, VIC, Australia
Organ fibrosis is a pathological condition associated with chronic inflammatory diseases. In fibrosis, excessive deposition of extracellular matrix (ECM) severely impairs tissue architecture and function, eventually resulting in organ failure. This process is mediated primarily by the induction of myofibroblasts, which produce large amounts of collagen I, the main component of the ECM. Accordingly, the origin, developmental pathways, and mechanisms of myofibroblast regulation are attracting increasing attention as potential therapeutic targets. The fibrotic cascade, from initial epithelial damage to eventual myofibroblast induction, is mediated by complex biological processes such as macrophage infiltration, a shift from Th1 to Th2 phenotype, and by inflammatory mediators such as transforming growth factor-β. Here, we review the current understanding of the cellular and molecular mechanisms underlying organ fibrosis.
http://www.frontiersin.org/Journal/1...00071/abstract
Folliculitis is defined histologically as the presence of inflammatory cells within the wall and ostia of the hair follicle, creating a follicular-based pustule. The actual type of inflammatory cells can vary and may be dependent on the etiology of the folliculitis, the stage at which the biopsy specimen was obtained, or both. The inflammation can be either limited to the superficial aspect of the follicle with primary involvement of the infundibulum or the inflammation can affect both the superficial and deep aspect of the follicle. Deep folliculitis can eventuate from chronic lesions of superficial folliculitis or from lesions that are manipulated, and this may ultimately result in scarring.
Perifolliculitis, on the other hand, is defined as the presence of inflammatory cells in the perifollicular tissues and can involve the adjacent reticular dermis. Folliculitis and perifolliculitis can manifest independently or together as a result of follicular disruption and irritation.
Two 4 mm punch biopsies were performed on the occiput of the 7 controls and the wound was closed with 3-0 polyglactin 910.
Hair transplant strip showing marked perifollicular fibrosis
Evaluation of perifollicular inflammation of donor area during hair transplantation in androgenetic alopecia and its comparison with controls
Background: Mild perifollicular inflammation is seen in both androgenetic alopecia (Androgenetic Alopecia) cases and normal controls, whereas moderate or dense inflammation with concentric layers of collagen, is seen in Androgenetic Alopecia cases but only in very few normal controls, and may lessen the response to topical minoxidil. Moderate or dense lymphocytic inflammation and perifollicular fibrosis have poor hair growth following transplantation. Aim: The purpose of the study is to evaluate the perifollicular lymphocytic inflammation and fibrosis in Androgenetic Alopecia patients during follicular unit hair transplantation (FUT) and its comparison in normal controls. Materials and Methods: A total of 21 male patients with Androgenetic Alopecia and 7 matched controls participated in the study. Histopathological analysis of biopsy specimens from donor strip of patients during the hair transplantation and two 4 mm punch biopsies on controls were performed. Morphometric analysis was performed and perifollicular fibrosis was scored based on the width of the condensed collagen at the lower infundibulum and isthmus from 0 to 3. Perifollicular infiltrate was also scored 0-3 and a total score of 3 or more out of 6 was considered significant. Results: Nearly 76% of Androgenetic Alopecia patients had perifollicular fibrosis more than 50 μm at ×200 magnification. Almost 33.33% patients had moderate/dense perifollicular lymphocytic infiltrate whereas none of the controls had it. Total score in Androgenetic Alopecia cases was significantly higher than controls (P = 0.012) using Chi-square test. Out of 21 patients, 13 had a score of 3 or more and were followed-up with monthly treatment with intralesional steroids using a dermaroller. Conclusion: Histopathological evaluation of the donor area is a must during hair transplantation to evaluate the extent of perifollicular inflammation and achieve better results by following it up with treatment directed to decrease the inflammation.
They are achieving better regrowth with topical anti-inflammatory during hair transplant..This is indeed, really interesting.
http://www.ijtrichology.com/article....st=Nirmal#ref6
Quantitative and ultrastructural analysis of inflammatory infiltrates in male pattern alopecia.
Sueki H, Stoudemayer T, Kligman AM, Murphy GF.
Author information
Abstract
In order to determine whether lymphocytic inflammation around the lower infundibula in male pattern alopecia is incidental or a general phenomenon, we performed morphometric and ultrastructural analysis of inflammatory infiltrates in the transitional zones of the vertex and occipital hairy scalps of 19 patients with male pattern alopecia. Six normal subjects served as controls. The number of inflammatory infiltrates around the follicular infundibula of the alopecic vertices and non-alopecic occiputs of male pattern alopecia patients was significantly greater than the corresponding control value. The number of mast cells in the widened fibrous tracts in the vertices of male pattern alopecia patients was significantly greater than those in the adventitial fibrotic sheaths of control subjects and the non-alopecic occiputs of male pattern alopecia patients. These data support the idea that the inflammatory process may be, at least in part, responsible for the development of male pattern alopecia.
Evaluation of perifollicular inflammation of donor area during hair transplantation in androgenetic alopecia and its comparison with controls
Background: Mild perifollicular inflammation is seen in both androgenetic alopecia (Androgenetic Alopecia) cases and normal controls, whereas moderate or dense inflammation with concentric layers of collagen, is seen in Androgenetic Alopecia cases but only in very few normal controls, and may lessen the response to topical minoxidil. Moderate or dense lymphocytic inflammation and perifollicular fibrosis have poor hair growth following transplantation. Aim: The purpose of the study is to evaluate the perifollicular lymphocytic inflammation and fibrosis in Androgenetic Alopecia patients during follicular unit hair transplantation (FUT) and its comparison in normal controls. Materials and Methods: A total of 21 male patients with Androgenetic Alopecia and 7 matched controls participated in the study. Histopathological analysis of biopsy specimens from donor strip of patients during the hair transplantation and two 4 mm punch biopsies on controls were performed. Morphometric analysis was performed and perifollicular fibrosis was scored based on the width of the condensed collagen at the lower infundibulum and isthmus from 0 to 3. Perifollicular infiltrate was also scored 0-3 and a total score of 3 or more out of 6 was considered significant. Results: Nearly 76% of Androgenetic Alopecia patients had perifollicular fibrosis more than 50 μm at ×200 magnification. Almost 33.33% patients had moderate/dense perifollicular lymphocytic infiltrate whereas none of the controls had it. Total score in Androgenetic Alopecia cases was significantly higher than controls (P = 0.012) using Chi-square test. Out of 21 patients, 13 had a score of 3 or more and were followed-up with monthly treatment with intralesional steroids using a dermaroller. Conclusion: Histopathological evaluation of the donor area is a must during hair transplantation to evaluate the extent of perifollicular inflammation and achieve better results by following it up with treatment directed to decrease the inflammation.
They are achieving better regrowth with topical anti-inflammatory during hair transplant..This is indeed, really interesting.
http://www.ijtrichology.com/article....st=Nirmal#ref6
Quantitative and ultrastructural analysis of inflammatory infiltrates in male pattern alopecia.
Sueki H, Stoudemayer T, Kligman AM, Murphy GF.
Author information
Abstract
In order to determine whether lymphocytic inflammation around the lower infundibula in male pattern alopecia is incidental or a general phenomenon, we performed morphometric and ultrastructural analysis of inflammatory infiltrates in the transitional zones of the vertex and occipital hairy scalps of 19 patients with male pattern alopecia. Six normal subjects served as controls. The number of inflammatory infiltrates around the follicular infundibula of the alopecic vertices and non-alopecic occiputs of male pattern alopecia patients was significantly greater than the corresponding control value. The number of mast cells in the widened fibrous tracts in the vertices of male pattern alopecia patients was significantly greater than those in the adventitial fibrotic sheaths of control subjects and the non-alopecic occiputs of male pattern alopecia patients. These data support the idea that the inflammatory process may be, at least in part, responsible for the development of male pattern alopecia.
| Article: Perifollicular fibrosis: pathogenetic role in androgenetic alopecia. Source: Biol Pharm Bull. 2006 Jun;29(6):1246-50. Author(s): Yoo HG, Kim JS, Lee SR, Pyo HK, Moon HI, Lee JH, Kwon OS, Chung JH, Kim KH, Eun HC, Cho KH Department of Dermatology, Seoul National University College of Medicine, Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, and Institute of Dermatological Science, Seoul National University. |
Summary:
Fibrosis is a scarring process in the skin that can damage the hair follicle (hair loss). This study shows that increased Testosterone speeds up fibrosis while treatment with Finasteride helps slow fibrosis. Stopping or slowing fibrosis may be another method by which Finasteride may help prevent hair loss.
Fibrosis is a scarring process in the skin that can damage the hair follicle (hair loss). This study shows that increased Testosterone speeds up fibrosis while treatment with Finasteride helps slow fibrosis. Stopping or slowing fibrosis may be another method by which Finasteride may help prevent hair loss.
| Androgenetic alopecia (Androgenetic Alopecia) is a dihydrotestosterone (DHT)-mediated process, characterized by continuous miniaturization of androgen reactive hair follicles and accompanied by perifollicular fibrosis of follicular units in histological examination. Testosterone (T: 10(-9)-10(-7) M) treatment increased the expression of type I procollagen at mRNA and protein level. Pretreatment of finasteride (10(-8) M) inhibited the T-induced type I procollagen expression at mRNA (40.2%) and protein levels (24.9%). T treatment increased the expression of transforming growth factor-beta 1 (TGF-beta1) at protein levels by 81.9% in the human scalp dermal fibroblasts (DFs). Pretreatment of finasteride decreased the expression of TGF-beta1 protein induced by an average of T (30.4%). The type I procollagen expression after pretreatment of neutralizing TGF-beta1 antibody (10 mug/ml) was inhibited by an average of 54.3%. Our findings suggest that T-induced TGF-beta1 and type I procollagen expression may contribute to the development of perifollicular fibrosis in the Androgenetic Alopecia, and the inhibitory effects on T-induced procollagen and TGF-beta1 expression may explain another possible mechanism how finasteride works in Androgenetic Alopecia. http://www.derma-haarcenter.ch/files...+Barcelona.pdf |
Cosmet Dermatol. 2009 Jun;8(2):83-91
Androgenetic alopecia in males: a histopathological and ultrastructural study.
El-Domyati M, Attia S, Saleh F, Abdel-Wahab H.
Department of Dermatology, Faculty of Medicine, Al-Minya University, Al-Minya, Egypt.
Background Androgenetic alopecia is a common cosmetic hair disorder, resulting from interplay of genetic, endocrine, and aging factors leading to a patterned follicular miniaturization. Microinflammation seems to be a potential active player in this process. Aims To study the histopathological and ultrastructural changes occurring in male androgenetic alopecia (Androgenetic Alopecia). Patients/methods Fifty-five subjects were included in this study (40 with Androgenetic Alopecia and 15 as normal age-matched controls). Skin biopsies from frontal bald area and occipital hairy area were subjected to histopathological examination, immunohistochemical staining for collagen I and ultrastructural study. Results The frontal bald area of patients showed highly significant increase in telogen hairs and decrease in anagen/telogen ratio and terminal/vellus hair ratio (P < 0.001). Perifollicular inflammation was almost a constant feature in early cases and showed a significant correlation with perifollicular fibrosis (P = 0.048), which was more marked with thickening of the follicular sheath in advanced cases. Conclusion Follicular microinflammation plays an integral role in the pathogenesis of Androgenetic Alopecia in early cases. Over time, thickening of perifollicular sheath takes place due to increased deposition of collagen, resulting in marked perifollicular fibrosis, and sometimes ends by complete destruction of the affected follicles in advanced cases.
http://www.biomediclaser.com/pdf/Inf...c-Alopecia.pdf
Formation of fibrous tissue or fibroplasia of the dermal sheath, which surrounds the hair follicle, is now suspected to be a common terminal process resulting in the
miniaturization. Involution of the pilosebaceous unit in this form of baldness and sustained microscopic
follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is
considered a possible cofactor in the complex etiology of androgenetic alopecia. However, till date, the
inflammatory component has not been explored in developing treatment protocols for androgenetic
alopecia.
Fibrosing Alopecia in a Pattern DistributionPatterned Lichen Planopilaris or Androgenetic Alopecia With a Lichenoid Tissue Reaction Pattern?
Patients developed progressive fibrosing alopecia of the central scalp, without the multifocal areas of involvement typical of lichen planopilaris and pseudopelade. Perifollicular erythema, follicular keratosis, and loss of follicular orifices were limited to a patterned area of involvement. Biopsy specimens of early lesions demonstrated hair follicle miniaturization and a lichenoid inflammatory infiltrate targeting the upper follicle region. Advanced lesions showed perifollicular lamellar fibrosis and completely fibrosed follicular tracts indistinguishable from end-stage lichen planopilaris, pseudopelade, or follicular degeneration syndrome.
http://archderm.jamanetwork.com/article.aspx?articleid=189906
INFLAMMATORY PHENOMENA AND FIBROSIS
The implication of microscopic follicular inflammation in the pathogenesis of Androgenetic Alopecia has emerged from several independent studies: An early study referred to an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles, associated with an enlargement of the follicular dermal sheath composed of collagen bundles (perifollicular fibrosis), in regions of actively progressing alopecia.[25] Horizontal section studies of scalp biopsies indicated that the perifollicular fibrosis is generally mild, consisting of loose, concentric layers of collagen that must be distinguished from cicatricial alopecia.[26] The term 'microinflammation' has been proposed, because the process involves a slow, subtle, and indolent course, in contrast to the inflammatory and destructive process in the classical inflammatory scarring alopecias.[27] The significance of these findings has remained controversial. However, morphometric studies in patients with male pattern Androgenetic Alopecia treated with minoxidil showed that 55% of those with microinflammation had regrowth in response to treatment, in comparison to 77% in those patients without inflammation and fibrosis.[26] Moreover, some forms of primary fibrosing alopecia may represent pathological exaggeration of Androgenetic Alopecia associated with follicular inflammation and fibrosis, specifically postmenopausal frontal fibrosing alopecia,[28] and fibrosing alopecia in a pattern distribution.[29]
An important question is how the inflammatory reaction pattern is generated around the individual hair follicle. Inflammation is regarded as a multistep process which may start from a primary event. Some authors proposed that alopecia may result from cumulative physiological degeneration of selected hair follicles. They described in healthy murine skin clusters of perifollicular macrophages as perhaps indicating the existence of a physiological program of immunologically controlled hair follicle degeneration by which malfunctioning follicles are removed by programmed organ deletion, and suggested that perhaps an exaggerated form of this process might underlie some forms of primary scarring alopecia.[30] The observation of a perifollicular infiltrate in the upper follicle near the infundibulum of human hair follicles in Androgenetic Alopecia suggests that the primary causal event for the triggering of inflammation might occur near the infundibulum.[27] On the basis of this localization and the microbial colonization of the follicular infundibulum with Propionibacterium sp., Staphylococcus sp., Malassezia sp., or other members of the transient flora, one could speculate that microbial toxins or antigens could be involved in the generation of the inflammatory response. Alternatively, keratinocytes themselves may respond to oxidative stress from irritants, pollutants, and UV irradiation, by producing nitric oxide, and by releasing intracellularly stored IL-1α. This pro-inflammatory cytokine by itself has been shown to inhibit the growth of isolated hair follicles in culture. [31] Moreover, adjacent keratinocytes, which express receptors for IL-1, start to engage the transcription of IL-1 responsive genes: mRNA coding for IL-1β, TNFα, and IL-1α, and for specific chemokine genes, such as IL-8, and monocyte chemoattractant protein-1 (MCP-1) and MCP-3, themselves mediators for the recruitment of neutrophils and macrophages, have been shown to be upregulated in the epithelial compartment of the human hair follicle.[27] Besides, adjacent fibroblasts are also fully equipped to respond to such a pro-inflammatory signal. The upregulation of adhesion molecules for blood-borne cells in the capillary endothelia, together with the chemokine gradient, drives the transendothelial migration of inflammatory cells, which include neutrophils through the action of IL-8, T cells, and Langerhans cells at least in part through the action of MCP-1. After processing of localized antigen, Langerhans cells, or alternatively keratinocytes, which may also have antigen presenting capabilities, could then present antigen to newly infiltrating T lymphocytes and induce T-cell proliferation. The antigens are selectively destroyed by infiltrating macrophages, or natural killer cells. On the occasion that the causal agents persist, sustained inflammation is the result, together with connective tissue remodeling, where collagenases, such as matrix metalloproteinase (also transcriptionally driven by pro-inflammatory cytokines) play an active role.[27] Collagenases are suspected to contribute to the tissue changes in perifollicular fibrosis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929555/
Androgen Alopecia is a big cluster****.. and yeah the problem seems deeper that what most people think. Biopsies image vertical sectioning.
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Fibroplasia was noted, characterized by an increased number of fibroblasts and increased amounts of collagen around the sebaceous glands and collagenous streamers [ 9 ], in 62% of subjects (Figs. 4 , 5 and 6 ). .
http://www.springerimages.com/Images...3-003-0447-y-3
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Scalp pathology in androgenetic alopecia: horizontal section. Severe peri-isthmus and peri-sebaceous lymphocytic infiltrates with perifollicular fibrosis (HE ×60)
http://www.springerimages.com/Images...3-003-0447-y-7
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Scalp pathology in androgenetic alopecia: vertical section. Mild perifollicular fibrosis in the dermis (HE ×70)
http://www.springerimages.com/Images...3-003-0447-y-3
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http://openi.nlm.nih.gov/detailedres...108-g015&req=4
Androgenetic Alopecia is characterized by progressive miniaturization of hair follicles. When the biopsy specimen is sectioned transversely at the level of opening of sebaceous ducts into the hair follicle, the hairs shafts appear vastly different in diameter. The position of the original terminal follicle is indicated by a follicular streamer (stellae or fibrous tract) extending from the subcutaneous tissue up to the course of the follicle to the miniaturized hair. Decreased terminal hairs and increased follicular streamers therefore characterize Androgenetic Alopecia. Sebaceous glands seem enlarged in relation to the miniaturized hair follicles. There is significant reduction in total follicular counts, measured by horizontal sectioning of scalp biopsy. The progressive reduction in the duration of anagen causes a relative increase in telogen hair [Figures 13‐15].
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Some good links for more biopsies pictures..
http://www.dermpedia.org/dermpedia-textbook/androgenic-alopecia
http://www.dermaamin.com/site/histop...alopecia-.html
Really cool biopsies from healthy and Androgenic Alopecia scalps...click on the link for the pics..
https://www.inkling.com/read/mckees-...on-of-alopecia
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Histological features of peripilar signs associated with androgenetic alopecia.
Deloche C, de Lacharrière O, Misciali C, Piraccini BM, Vincenzi C, Bastien P, Tardy I, Bernard BA, Tosti A.
Source
Centre Charles Zviak, L'Oréal Recherche, 90 rue du Général Roguet, 92583 Clichy Cedex, France.
Abstract
BACKGROUND:
A study of the scalp in a large cohort of volunteers with androgenetic alopecia using macrophotographs showed the presence of peripilar signs (PPS) around the hair ostia.
OBJECTIVE:
The aim of the present study was to establish the histopathological features related to PPS.
DESIGN:
Prospective clinicopathological study. SETTING. Department of Dermatology, University Hospital of Bologna.
PATIENTS:
A group of 40 patients (21 males and 19 females) participated in the study. Macrophotographs of the scalp were taken using a Dermaphot camera and PPS were scored using a three-point scale. Hair density and PPS were clinically scored according to reference scales. Two punch biopsies from the photographed area were obtained from each subject and histological analysis was performed on vertical and horizontal sections.
OBSERVATIONS:
Clinical parameters indicated that PPS were already detectable on scalp with high hair density. Moreover, in patients with high hair density (score >4), a significant relationship was found between the PPS score and the global score for perifollicular infiltrates. Thus PPS are linked to superficial perifollicular lymphocytic infiltrates in early androgenetic alopecia.
CONCLUSIONS:
PPS could be the clinical signs reflecting the presence of perifollicular infiltrates.
Scalp dermoscopy of androgenetic alopecia in Asian people.
Inui S, Nakajima T, Itami S.
Source
Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Abstract
Although dermoscopy is used mainly for diagnosing pigmented skin lesions, this device has been reported to be useful in observing alopecia areata and frontal fibrosing alopecia. Herein, we investigated the dermoscopic features and their incidence of androgenetic alopecia (Androgenetic Alopecia; n = 50 men) and female Androgenetic Alopecia (***A; n = 10 women) in Asian people. More than 20% hair diameter diversity (HDD), which reportedly is an early sign of Androgenetic Alopecia and corresponds to hair follicle miniaturization, was observed in the affected area of all Androgenetic Alopecia and ***A cases, suggesting that HDD is an essential feature to diagnose Androgenetic Alopecia and ***A. Peripilar signs, corresponding to perifollicular pigmentation, were seen in 66% (33/50) of Androgenetic Alopecia and 20% (2/10) of ***A women. This incidence in the present study was lower than previously reported in white subjects possibly because the Asian skin color conceals slight peripilar pigmentation. Yellow dots were observed in 26% (13/50) of Androgenetic Alopecia and 10% (1/10) of ***A cases and the number of yellow dots in Androgenetic Alopecia and ***A was limited to 10 on the overall hair loss area. Yellow dots possibly indicate the coincidence of Androgenetic Alopecia and enlargement of the sebaceous glands caused by common end-organ hypersensitivity to androgen. In conclusion, dermoscopy is useful to diagnose Androgenetic Alopecia and ***A and provides insights into the pathogenesis of Androgenetic Alopecia.
“During the hair cycle the follicle has to be rebuilt from stem cells,” explains Dr Bruno Bernard, director of research for life sciences at L’Oreal. “Stem cells in human hair follicles are localised in two different reservoirs – one is in the upper part of the follicle and the other in the lower part.
“The cells in the lower part are required to activate the cells in the upper part and so help to maintain the follicle function. The thickening of collagen in the connective tissue sheath, which sits around the base of the hair follicle, prevents the movement of stem cells from the lower reservoir to the upper reservoir. Bit by bit, the follicle is squeezed and causes the follicles to grow smaller and smaller.” Indeed, research from The Rockefeller University in New York suggests movement between the two groups of stem cells is crucial in normal hair growth.
http://www.telegraph.co.uk/science/8...he-corner.html
. [SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1][SIZE=-1]Perifollicular sheath is the major problem in Androgen Alopecia.[/SIZE][/SIZE][/SIZE][/SIZE][/SIZE]
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Male pattern alopecia a histopathologic and histochemical study.
Lattanand A, Johnson WC.
Abstract
Three hundred and forty-seven tissue specimens were studied from 23 patients with male pattern alopecia. Characteristic features of pattern alopecia included: the presence of miniature or vellus follicles; a marked enlargement of the sebaceous glands and arrectores pilorum muscles; the presence of connective tissue streamers beneath the vellus follicles; and the thinning of the dermis. A mild perivascular infiltrate of mononuclear cells and mild capillary dilatation was sometimes seen. An increased number of mast cells was often a prominent feature. Histochemical procedures were performed for glycogen, acid mucosaccharides, inorganic substances, and enzymes including alkaline phosphatase, acid phosphatase, beta glucuronidase, cholinesterase, aminopeptidase, oxidases and dehydrogenases. Histochemical studies did not reveal any significantly abnormal enzyme changes other than the altered vascular and nerve supply to the the miniature follicles.
J Drugs Dermatol. 2011 Dec;10(12):1404-11.
The role of inflammation and immunity in the pathogenesis of androgenetic alopecia.
Magro CM, Rossi A, Poe J, Manhas-Bhutani S, Sadick N.
Author information
Abstract
BACKGROUND:
Female pattern hair loss affects many women; its pathogenetic basis has been held to be similar to men with common baldness.
OBJECTIVE:
The objective of this study was to determine the role of immunity and inflammation in androgenetic alopecia in women and modulate therapy according to inflammatory and immunoreactant profiles.
MATERIALS AND METHODS:
52 women with androgenetic alopecia (AA) underwent scalp biopsies for routine light microscopic assessment and direct immunofluroescent studies. In 18 patients, serologic assessment for antibodies to androgen receptor, estrogen receptor and cytokeratin 15 was conducted.
RESULTS:
A lymphocytic folliculitis targeting the bulge epithelium was observed in many cases. Thirty-three of 52 female patients had significant deposits of IgM within the epidermal basement membrane zone typically accompanied by components of complement activation. The severity of changes light microscopically were more apparent in the positive immunoreactant group. Biopsies from men with androgenetic alopecia showed a similar pattern of inflammation and immunoreactant deposition. Serologic assessment for antibodies to androgen receptor, estrogen receptor or cytokeratin 15 were negative. Combined modality therapy with minocycline and topical steroids along with red light produced consistent good results in the positive immunoreactant group compared to the negative immunoreactant group.
CONCLUSION:
A lymphocytic microfolliculitis targeting the bulge epithelium along with deposits of epithelial basement membrane zone immunoreactants are frequent findings in androgenetic alopecia and could point toward an immunologically driven trigger. Cases showing a positive immunoreactant profile respond well to combined modality therapy compared to those with a negative result.
Acute Inflammation ( Induced by the derma roller)
Acute inflammation is a normal process that protects and heals the body following physical injury or infection. Acute inflammation involves local dilation of blood vessels as well as increased vessel permeability to improve blood flow to the injured area. At the site of an infection or injury, mast cells, platelets, nerve endings, endothelial cells, and other resident cells release signaling molecules and chemoattractants that recruit leukocytes to the affected area. Neutrophils, a type of granulocyte, are the first leukocytes to appear at the injured site. These cells phagocytose (engulf) and kill invading microorganisms through the release of non-specific toxins, such as superoxide radicals, hypochlorite, and hydroxyl radicals; these reactive oxygen species (ROS) kill pathogens as well as adjacent cells, sick and healthy alike. Neutrophils also release cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, gamma interferon (INF-gamma), and others. Such pro-inflammatory cytokines in turn induce the liver to synthesize various acute phase reactant proteins and also induce systemic inflammatory responses (e.g., fever and leukocytosis—a rise in the number of white blood cells). Neutrophils are short-lived and are thus primarily involved in the early stages of inflammation.
Hemostasis:
Once the source of damage to a house has been removed and before work can start, utility workers must come in and cap damaged gas or water lines. So too in wound healing damaged blood vessels must be sealed. In wound healing the platelet is the cell which acts as the utility worker sealing off the damaged blood vessels. The blood vessels themselves constrict in response to injury but this spasm ultimately relaxes. The platelets secrete vasoconstrictive substances to aid in this process but their prime role is to form a stable clot sealing the damaged vessel. Under the influence of ADP (adenosine diphosphate) leaking from damaged tissues the platelets aggregate and adhere to the exposed collagen. They also secrete factors which interact with and stimulate the intrinsic clotting cascade through the production of thrombin, which in turn initiates the formation of fibrin from fibrinogen. The fibrin mesh strengthens the platelet aggregate into a stable hemostatic plug. Finally platelets also secrete cytokines such as platelet-derived growth factor (PDGF), which is recognized as one of the first factors secreted in initiating subsequent steps. Hemostasis occurs within minutes of the initial injury unless there are underlying clotting disorders.
Inflammation Phase:
Clinically inflammation, the second stage of wound healing presents as erythema, swelling and warmth often associated with pain, the classic “rubor et tumor c*m calore et dolore”. This stage usually lasts up to 4 days post injury. In the wound healing analogy the first job to be done once the utilities are capped is to clean up the debris. This is a job for non-skilled laborers. These non-skilled laborers in a wound are the neutrophils or PMN’s (polymorphonucleocytes). The inflammatory response causes the blood vessels to become leaky releasing plasma and PMN’s into the surrounding tissue. The neutrophils phagocytize debris and microorganisms and provide the first line of defense against infection. They are aided by local mast cells. As fibrin is broken down as part of this clean-up the degradation products attract the next cell involved. The task of rebuilding a house is complex and requires someone to direct this activity or a contractor. The cell which acts as “contractor” in wound healing is the macrophage. Macrophages are able to phagocytize bacteria and provide a second line of defense. They also secrete a variety of chemotactic and growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-__ and interleukin-1 (IL-1) which appears to direct the next stage.
Proliferative Phase ( Proliferation, Granulation and Contraction):
The granulation stage starts approximately four days after wounding and usually lasts until day 21 in acute wounds depending on the size of the wound. It is characterized clinically by the presence of pebbled red tissue in the wound base and involves replacement of dermal tissues and sometimes subdermal tissues in deeper wounds as well as contraction of the wound. In the wound healing analogy once the site has been cleared of debris, under the direction of the contractor, the framers move in to build the framework of the new house. Sub-contractors can now install new plumbing and wiring on the framework and siders and roofers can finish the exterior of the house. The “framer” cells are the fibroblasts which secrete the collagen framework on which further dermal regeneration occurs. Specialized fibroblasts are responsible for wound contraction. The “plumber” cells are the pericytes which regenerate the outer layers of capillaries and the endothelial cells which produce the lining. This process is called angiogenesis. The “roofer” and “sider” cells are the keratinocytes which are responsible for epithelialization. In the final stage of epithelializtion, contracture occurs as the keratinocytes differentiate to form the protective outer layer or stratum corneum.
Remodeling or Maturation Phase:
Once the basic structure of the house is completed interior finishing may begin. So too in wound repair the healing process involves remodeling the dermal tissues to produce greater tensile strength. The principle cell involved in this process is the fibroblast. Remodeling can take up to 2 years after wounding and explains why apparently healed wounds can break down so dramatically and quickly if attention is not paid to the initial causative factors.
Chronic Inflammation ( Androgen Alopecia)
If the stimulus persists, inflammation can last days, months, and even years. Chronic inflammation is primarily mediated by monocytes and long-lived macrophages; monocytes mature into macrophages once they leave the bloodstream and enter tissues. Macrophages engulf and digest microorganisms, foreign invaders, and senescent cells. Macrophages release several different chemical mediators, including IL-1, TNF-alpha, and prostaglandins, that perpetuate the pro-inflammatory response. At later stages, other cells, including lymphocytes, invade the affected tissues: T lymphocytes kill virus-infected cells and B lymphocytes produce antibodies that specifically target the invading microorganisms for destruction.
Macrophages and other leukocytes release ROS and proteases that destroy the source of inflammation; however, damage to the body's own tissues often results. In fact, tissue damage is a hallmark of chronic inflammation. Another characteristic of chronic inflammation is repair of the damaged tissue by replacement with cells of the same type or with fibrous connective tissue. An important part of the inflammatory process involves local angiogenesis—the development of new blood vessels. In some instances, the body is unable to repair tissue damage, and the inflammatory cascade continues. Chronic inflammation is abnormal and does not benefit the body; in fact, chronic inflammation is involved in a number of disease states.
http://www.vetmed.vt.edu/education/...thology/INFLAMMATION LAB/INFLAMMATION LAB.htm
Prostaglandin D[SUB]2[/SUB] Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/
Markers and Mediators of Inflammation
Nuclear factor kappa-B (NF-kB) is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-kB, which turns on the expression of over 400 genes involved in the inflammatory response (Sethi et al. 2008). These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex®).
http://en.wikipedia.org/wiki/NF-κB
Tumor necrosis factor alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells) (Green et al. 1976), TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types (Sethi et al. 2008). Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion (Kundu et al. 2008).
http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha
Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.
http://en.wikipedia.org/wiki/Interleukin
C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells (Meyer 2010). CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections (Windgassen et al. 2011). Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke (Emerging Risk Factors Collaboration et al. 2010).
http://en.wikipedia.org/wiki/C-reactive_protein
Eicosanoids. The cytokine factors mentioned above (interleukins, TNF-α) are “long-distance messages”. They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses (Luo et al. 2011). There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.
Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes (see below) (Serhan et al. 2001).
http://en.wikipedia.org/wiki/Eicosanoid
Cyclooxygenases and Lipoxygenases. The eicosanoids (above) require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and the non-steroidal anti- inflammatory drugs (NSAIDS, like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process: it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.
http://en.wikipedia.org/wiki/Cyclooxygenase
Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response (Luo et al. 2011). Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy
While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins), The proper transition from the pro- to anti-inflammatory activities of the COX and LOX enzymes is an important for the progression of a healthy inflammatory response.
http://en.wikipedia.org/wiki/Lipoxygenase
