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Oud 7 januari 2007, 09:20   #1
DHTkiller
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Relaxin

Ik heb via google veel informatie kunnen vinden over het hormoon relaxin. Relaxin wordt bij zwangere vrouwen in hoge mate aangemaakt om de bevalling later mogelijk te maken. Het maakt de bindweefsel in de bekken soepeler om dus zo de bevalling mogelijk te maken. Relaxin verwijdt ook de bloedvaten en gaat fibrosis tegen en maakt de huid elastischer. Op sommige sites wordt verondersteld dat het uitstekend kan werken tegen AGA. Nog mensen die wat meer weten over relaxine of het zelf al gebruiken (geheime experimentele middel van Kevin misschien )? Kevin, Tiuri?
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Oud 7 januari 2007, 13:42   #2
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Jawel

Hier een qoute:

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It promotes laminin-5 and MMP-2 (similar to Thymosin Beta 4), increases IGF-1, nitric oxide, and inhibits TGF-beta
Ik weet dat TGF-beta een grote rol speelt bij AGA en voornamelijk Fibrosis doordat het littekenvorming stimuleert. Hierdoor kan het haartje niet meer groeien.

Als je tijd hebt om alles door te lezen, staat hier en hier erg veel informatie om het te gebruiken bij AGA. Ik heb er geen zin in eigenlijk Maar het is best wel erg interessant allemaal.
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Oud 7 januari 2007, 15:14   #3
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Het zou sowieso erg fijn zijn als we eens een manier weten te vinden om ook maar iets tegen Fibrose te doen. Het is een reden dat haar uitvalt, maar vooral een van de hoofdredenen dat hergroei niet meer kan plaatsvinden.

Een tijdje terug las ik een artikel dat geschreven zou zijn door een van de onderzoekers naar RU en de werking daarvan bij makaken. Volgens hem is een belangrijke reden dat Ru bij de apen wél goed werkte en bij mensen later niets bleek te doen, het feit dat bij de apen geen fibrose-vorming plaatsvond tijdens het kalingsproces en bij mensen wel.
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Oud 7 januari 2007, 15:22   #4
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Oorspronkelijk geplaatst door Vince001
Het zou sowieso erg fijn zijn als we eens een manier weten te vinden om ook maar iets tegen Fibrose te doen. Het is een reden dat haar uitvalt, maar vooral een van de hoofdredenen dat hergroei niet meer kan plaatsvinden.

Een tijdje terug las ik een artikel dat geschreven zou zijn door een van de onderzoekers naar RU en de werking daarvan bij makaken. Volgens hem is een belangrijke reden dat Ru bij de apen wél goed werkte en bij mensen later niets bleek te doen, het feit dat bij de apen geen fibrose-vorming plaatsvond tijdens het kalingsproces en bij mensen wel.
Interessant zeg, kevin & Vince. Goeie posts weer.

Heb je toevallig nog een linkje naar dat artikel, Vince?
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Oud 7 januari 2007, 15:28   #5
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Oorspronkelijk geplaatst door Vince001
Het zou sowieso erg fijn zijn als we eens een manier weten te vinden om ook maar iets tegen Fibrose te doen. Het is een reden dat haar uitvalt, maar vooral een van de hoofdredenen dat hergroei niet meer kan plaatsvinden.

Een tijdje terug las ik een artikel dat geschreven zou zijn door een van de onderzoekers naar RU en de werking daarvan bij makaken. Volgens hem is een belangrijke reden dat Ru bij de apen wél goed werkte en bij mensen later niets bleek te doen, het feit dat bij de apen geen fibrose-vorming plaatsvond tijdens het kalingsproces en bij mensen wel.
Copper Peptides zijn de enige bewezen middelen tegen Fibrosis. En inderdaad Vince, dat heette volgens mij (micro)inflammation.
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Oud 7 januari 2007, 15:40   #6
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Oorspronkelijk geplaatst door kevin
Copper Peptides zijn de enige bewezen middelen tegen Fibrosis. En inderdaad Vince, dat heette volgens mij (micro)inflammation.
Niet helemaal. Ook Minoxidil gaat fibrose tegen. En Aminexil richt zich op fibrose. Tiuri liet hier een keer zien dat de molecuul van Aminexil verdacht veel lijkt op die van Minoxidil. Ik denk dat ze bij LÓreal de minoxidil molecuul 'gesloopt' hebben om het fibrose werende deel te isoleren en te gebruiken voor Aminexil.

Vandaar dat Aminexil op zich niet zo veel kan uithalen. Fibrose is niet in hoofdlijnen de veroorzaker van haaruitval, maar bevorderd het proces flink en houdt de situatie van de uitgavallen haren stabiel door de littekenvorming.

Daarnaast schijnen er nog natuurlijke produkten te zijn die fibrosevorming tegengaan, maar volgens mij is daar nooit zo denderend onderzoek naar gedaan...
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Oud 7 januari 2007, 15:45   #7
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Oorspronkelijk geplaatst door Tiuri
Interessant zeg, kevin & Vince. Goeie posts weer.

Heb je toevallig nog een linkje naar dat artikel, Vince?
Zoals gezegd, kan ik het complete artikel niet meer vinden op regrowth.com. Misschien later via google. Ik heb in de thread over Omega3 ooit het benedestaande citaat neergelegd. Het gaat idd niet alleen over fibrosis, maar ook, zoals Kevin stelde, over inflammation.
Citaat:
Dr. Hideo Uno, one of the foremost experts in the world on MPB, explained that macaques respond more favorably to baldness treatments than do humans...especially to antiandrogen treatments, macaques get better and more consistent results because macaque baldness is purely a genetic and androgen-driven disease. Human baldness is much more complicated, hence decreased results and a whole range of responses to various treatments, due to the fact that human baldness involves inflammation and fibrosis. According to Uno, this is the key difference between macaque and human baldness, along with the fact that macaques are not exposed to other factors which inhibit hair growth, like stress, smoking, poor diets/insulin resistance, etc.

Laatst gewijzigd door Vince001; 7 januari 2007 om 15:54
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Oud 7 januari 2007, 16:13   #8
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Hier kun je dat artikel terugvinden Tiuri en Vince

Edit tiuri: LOL goed gevonden. Ik plak het even in deze post voordat we het weer kwijt zijn:

Citaat:
Here's that info for you Immortal.

This is a paragraph by a poster over at HLH. Good stuff, let me know what you think.

Paragraph 1:

Citaat:
" Here is a little something on the immune attack from Dr. Peter Proctor's (hairloss-researcher) website: "Emerging Model for Pattern Balding (after Kligman, others ) Balding begins when male sex hormones do "something " to the scalp hair follicle which causes it to be read as a "foreign body". Your immune system then mounts an attack on the hair folllicle. The main damage in pattern hair loss is probably immunologically-mediated. Damage to lining of blood vessels, which produces hair growth factors, makes the balding process worse. "
That info is from this page: http://www.drproctor.com/baldfaq1.htm

Check out what Proctor goes on to say

Citaat:
"Microscopically, balding looks like organ rejection. That is, increased number of immune system cells clustor round the base of the scalp hair follicle. Interestingly, lessor numbers of immune system cells normally cluster around the hair follicle. These may have a role in the normal hair cycle.

Organ rejection drugs ( e.g., cyclosporin ) reverse balding better than antiandrogens. This gives a rough indication of the relative importance of hormonal verses immunological factors in maintaining the balding state. Conversely, cyclosporin and similar agents may also have a "phenytoin-like" action on follicles which induces hair regrowth, separate from their immunosuppressive properties"
Proctor also discusses minoxidil, and why it works:

Citaat:
"Blood Vessel Lining in Pattern Hair Loss

Minoxidil, other agents apparently imitate hair growth factors ( nitric oxide radical, etc. ) produced by vessel lining. For a paper on this, go here. In diseases involving damage to vessel lining (e.g., atherosclerosis) production of these hair regrowth factors decreases. Such diseases are associated epidemiologically with severe balding. Also, decreases in circulation reported in balding scalp may reflect local damage to vessel linings. Alternately, some deficit in both the blood vessel and the hair follicle produces coincidental deterioration in both organs, producing hair loss. Again, a good candidate is the nitric oxide/superoxide system"
Paragraph 2:

This paragraph is from Uno's HISTOPATHOLGY OF HAIRLOSS and deals with the immuno attack:

Citaat:
"In alopecia skin, tha abnormal streamers underneath the follicles appear to be a structural barrier for the down-growth of anagen follicles. Moreover, severe inflammatory involvement in the streamers causes suppressive growth of the follicular bulb and dermal papilla cells. Dense collagenous or hyalinized scarring streamers block the growth of follicles. These follicular structures naturally resist any therapeutic effect for follicular growth. Moreover, associations of focal perivascular and perifollicular inflammatory cell infiltrations are often seen in alopecic skin."
A guy called THE ALMIGHTY GOD OF HAIRLOSS, who like Bryan Shelton, has read tons about the condition wrote the following paragraph about Uno's work with human vs. macaque baldness. I proboably learned more reading the following than I did in a couple of months research on my own (because TAGHL is alot smarter than I am). Enjoy:

Citaat:
Androgens, MPB, and human vs. macaques"

Guys,

Hideo Uno, an expert on MPB, published an OUTSTANDING paper on human vs. macaque baldness. I was very glad to read this paper, because it validates everything that I have said and thought regarding MPB.

If you read nothing else in this post, PLEASE (I beg you!) read the excerpts written by Hideo Uno, which are VERY, VERY important, and explains the key to fighting MPB in the most successful way possible. It also explains why some people don't respond to treatments like DUT. Anyone who wants a thorough understanding of human alopecia should read this entire post carefully!

This post will also prove what group of users are most credible in this forum. That is, it shows that myself, Bryan, Marco, Frizz, etc. have been right all long. The foremost experts in the world verify what we've been telling you all these months.

CommoneSense, I think Dr. Uno's statements are going to shock you, but more importantly, they are going to educate you on MPB. After reading his comments, I sincerely hope you change your outlook and recommendations on the treatment of MPB.

In this paper, Hideo Uno covers the histopathology of both macaque *AND* human baldness. Despite what some uninformed readers say, human baldness is a complicated disorder which involves more than just androgens.

Point number one: The histopathology of human and macaque baldness, while similar, HAVE SOME KEY DIFFERENCES.

We know that macaques respond more favorably to baldness treatments than do humans (especially to antiandrogen treatments). And we know that the response rate among macaques is remarkably consistent; i.e., they all get similar results (in contrast to humans, where we see greatly varying results among individuals).

So, why do macaques get better and more consistent results? Because macaque baldness is purely a genetic and androgen-driven disease. Human baldness is much more complicated, hence decreased results and a whole range of responses to various treatments.

Why is human baldness more complicated? For starters, human baldness involves inflammation and fibrosis. In macaque baldness, inflammation and fibrosis is absent among all macaques (source: Uno's study below). This is a key difference between macaque and human baldness. And since inflammation generates a slew of potent hair growth inhibitors (IL-1, TNF-alpha, TGF-beta1, etc.), and since fibrosis scars the structure of the follicle itself, this explains the difference in results between humans and macaques. Also, macaques are not exposed to other factors which inhibit hair growth, like stress, smoking, poors diets/insulin resistance, etc.

Don't believe me? Hideo Uno verifies everything I've said above. Keep reading....

Point number two: all of those who think that antiandrogens are the be-all and end-all of treatments are severely misguided, and do not understand the pathology of human pattern baldness.

In particular, CommonSense (and other like-minded readers) has long dismissed the involvment of factors other than androgens and genetics. He wants you to believe that androgens are the ONLY factor involved, and the ONLY factor we should address. Also, he continuously downplays any other approach to fighting MPB, such as antiinflammatory and anti-fibrotic treatments.

So, who to believe? Me, Bryan, Frizz, Marco, etc., or CommonSense? Well, I will let the experts tell you in their own words. To make a long story short, CS is completely misguided, and below is the proof from one of the foremost experts on hair loss in the world.

So, without further ado, here is some excerpts from Hideo Uno:

Citation:

Androgenetic alopecia in the stumptailed macaque: an important model for investigating the pathology and antiandrogenic therapy of male pattern baldness. Hideo Undo, etc. al. Chapter 11, Hair and its Disorders: Biology, Pathology and Management; published by Martin Dunitz Ltd, 2000.

Excerpts (in qoutes):

"... However, our recent comparative studies on the histopathology of human and macaque androgenetic alopecia revealed critical differences in pathological manifestations between these two counterparts (19)."

My comment: this next excerpt is a very important point that everyone should know about.

"The histopathological changes of the human androgenetic alopecia have been described by many investigators. Besides a miniaturization of follicles, fibrogranulomatous or collagenous streamers are beneath the follicles, together with focal perivascular and perifollicular inflammatory cell infiltrations, and varying degrees of fibrosis have been reported (Table 1)."

My comment: this next excerpt has more IMPORTANT details on human MPB, and why some people simply fail to respond to treatments.

"In alopecia skin, tha abnormal streamers underneath the follicles appear to be a structural barrier for the down-growth of anagen follicles. Moreover, severe inflammatory involvement in the streamers causes suppressive growth of the follicular bulb and dermal papilla cells (see Figure 8a). Dense collagenous or hyalinized scarring streamers block the growth of follicles (Figure 8b and c). These follicular structures naturally resist any therapeutic effect for follicular growth. Moreover, associations of focal perivascular and perofollicular inflammatory cell infiltrations are often seen in alopecic skin."

My comment: Dr. Uno now summarizes the pathology of macaque baldness. Please note that it is different than human alopecia in that hair loss develops evenly, whereas in humans there are many different patterns of hair loss, and that alopecia in macaques develops very rapidly, whereas in humans it's much, much slower. Additionally, there is NO INFLAMMATION IN macaque baldness.

"In the macaque, alopecia develops evenly in the entire frontal scalp during a relatively short period after the elevation of androgens during puberty. In the macaque alopecia, the histopathological changes comprise simply of miniaturization of the follicles, with those follicles remaining in telogen for a long period. There is no inflammatory involvement in the dermis and no adnormal streamers underneath the follicles, unlike the human counterpart."

My comment: Dr. Uno now says macaques respond better to treatments than humans, based on all of the available data.

"... However, presumably because of the different pathological backgrounds between macaque and human alopecia, macaque alopecia responded more strongly and homogeneously than human alopecia (Table 3)."

My comment: A VERY IMPORTANT, key point here by Dr. Uno.

"Furthermore, in human androgenetic alopecia, therapeutic approaches cannot simply rely on either hypertrichotic or antiandrogenic agents or even a combination of both. For further therapeutic improvement, it may be necessary to use combined treatment with antiandrogenic and antiinflammatory, as well as anti-fibrotic agents; hypertrichotic agents, such as minoxidil, or other potassium channel openers in addition, may enhance efficacy."

My comment: To sum it all up, here are Dr. Uno's conclusions. This paragraph is EXTREMELY IMPORTANT!!!!!!

"... Nonetheless, the complexity of the pathological changes in human androgenetic alopecia appears to hamper the effects of these hair growth-stimulating agents. Thus, results obtained from the macaque, which has no such complications, usually show much greater and homogeneous effects than those obtained in human alopecia. The pathologoical changes associated with regressed follicles in human androgenetic alopecia have been described by many investigators. However, more studies on the histogenesis of inflammatory streamers, dermal lymphocytic infiltrations, and the process of focal fibrotic changes are necessary to fully define this disorder. For further improvement of therapy, combined pharmacological interventions may be needed to reduce or prevent inflammatory and fibrotic processes in human alopecic skin."
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Laatst gewijzigd door Tiuri; 7 januari 2007 om 16:26
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Oud 7 januari 2007, 16:17   #9
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Hier wat opmerkingen over Fibrosis:

Citaat:
It has been hypothesised that itching is caused by the human immune system attacking the hair follicle, which leads to inflammation, fibrosis and eventually miniturization-a process commonly called MPB.

It's comforting news that Copper Peptides get rid of this itching completely and almost immediately.

This makes sense because studies with copper peptides have shown to get significantly reduce inflammation, halt and reverse fibrosis and slow down the immune response.

Itching is not always present in MPB, but inflammation and fibrosis are. So, just because you scalp feels fine isnt indication that you don't need to treat it.
Citaat:
The Comparative Histopathology of Male-Pattern Baldness and Senescent Baldness" Albert M. Kligman, MD, PhD

"All of the early MPB features are present. More of the shortened follicles are in telogen. The streamers still show considerable inflammation, but fibrosis is in greater evidence, with many parallel bundles of dense collagen. Occasional streamers eventually end up as fibrotic tracts. These are subfollicular scars. These fibrous bands have few cells, sparse vessels, and show hyalinized collagen. End-stage fibrosis of this degree is not common; surprisingly, some seem to undergo partial resorption, suggesting that they might disappear altogether...."

"MPB is a genetically determined inflammatory disorder that should not be considered as premature aging. The etiology of the inflammation is unknown. Follicular miniaturization in MPB is a consequence of pathologic fibrosis of the connective tissue sheath. The central pathology relates to abnormalities of the perifollicular connective tissue sheath, evident as inflamed streamers subtending involuting follicles. Those streamers show fibroplasia and hypertrophy, along with proliferation of capillaries and a mixed infiltrate of lymphocytes, histocytes, and mast cells. Chronic inflammation of the streamers prevents anagen follicles from being fully reconstructed during the new cycle. After many years, this can lead to scarring and preclude regeneration. Even in advanced MPB, most follicles were not fully scarred, offering the theoretical possibility of regrowth. Fibrotic streamers are increased in proportion to the duration of baldness and chronologic age".

As you see, inflammation and fibrosis are essential players in MPB. Cu Peptides are capable of preventing and even reversing tissue fibrosis.
Citaat:
The kind of inflammation and the fibrosis associated with MPB is triggered by androgens, and usually the only symptom is hair loss.

The only thing that i know of that can treat and reverse this is Copper Peptides.
Van user Bryan en JesusFreak op HLT.
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Laatst gewijzigd door kevin; 7 januari 2007 om 16:21
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Oud 7 januari 2007, 16:20   #10
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Ik blijf erbij dat je een Copper Peptide in je regime moet hebben om haaruitval maximaal te bestrijden. Vooral jij Tiuri
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Oud 7 januari 2007, 16:28   #11
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Oorspronkelijk geplaatst door kevin
Ik blijf erbij dat je een Copper Peptide in je regime moet hebben om haaruitval maximaal te bestrijden. Vooral jij Tiuri
Ik heb dat geprobeerd en kreeg er helaas enorme uitslag van.
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Oud 7 januari 2007, 16:30   #12
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Oorspronkelijk geplaatst door Tiuri
Ik heb dat geprobeerd en kreeg er helaas enorme uitslag van.
Dat was toch de shampoo? En heb je beiden geprobeert? Folligen en Tricomin? Er zijn gebruikers die een paar dagen tot een week een geirriteerde huid krijgen van Folligen, maar daarna trekt het bij en is het compleet over. Ook kun je Folligen 50/50 verdunnen volgens de maker.
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Oud 7 januari 2007, 16:49   #13
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Ik blijf het een interessant artikel/ post vinden. Zelf hecht ik er veel waarde aan, vooral omdat het probeert antwoord te geven op een aantal vragen waar men de laatste jaren de tanden op stuk beet, zoals waarom middelen in dieronderzoeken beter werken dan daadwerkelijk bij mensen en hoe belangrijk een gezonde hoofdhuid is.

Btw, op Regrowth.com zijn al een tijde discussies aan de gang ovder de eventuele rol van peeling bij het tegengaan van fibrose. Zelf dacht ik dat fibrose zich alleen in de haarwortel vormde, maar bij die discussie gaat men ervan uit dat dat op de gehele kaler wordende scalp gebeurt... Iemand hier ideeen over..?

Misschien moet ik toch ook maar weer terug naar de CopperPeptides. Ik had geen zin meer in Tricomin omdat het mij veel te licht spul leek.
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Oud 7 januari 2007, 22:42   #14
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Organ rejection drugs ( e.g., cyclosporin ) reverse balding better than antiandrogens
Dit is toch niet juist? Oke keto wordt wel gegeven bij orgaantransplantaties maar bij AGA werkt het anti androgeen.
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Oud 25 februari 2007, 21:57   #15
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Misschien moeten we toch maar eens een aparte thread openen voor fibrose en TGF-b e.d...? Hier iig weer iets over fibrose (/tgf-b1), hoe het werkt en de ontwikkeling van een topical. Ik zal 't later nog wel ff wat mooier neerzetten.. En ook zorgen dat ik het zelf helemaal gelezen heb
Citaat:
Topical Application of a Peptide Inhibitor of Transforming Growth Factor-1 Ameliorates Bleomycin-Induced Skin Fibrosis
Begoña Santiago*,1, Irene Gutierrez-Cañas*,1, Javier Dotor†, Guillermo Palao*, Juan José Lasarte†, Juan Ruiz‡, Jesús Prieto†, Francisco Borrás-Cuesta† and José L Pablos*

*Unidad de Investigación, Hospital 12 de Octubre, Madrid, Spain
†Division of Hepatology and Gene Therapy, Centre for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain
‡DIGNA Biotech, Madrid, Spain
Correspondence: José L. Pablos, Unidad de Investigación, Hospital 12 de Octubre, 28041 Madrid, Spain. Email: jlpablos@h12o.es

1B. Santiago and I. Gutierrez-Cañas contributed equally to this work.

Received 3 February 2005; Revised 15 April 2005; Accepted 13 May 2005.

Top of pageAbstract
Transforming growth factor- (TGF-) plays a crucial role in the pathogenesis of skin fibrotic diseases. Systemic TGF- inhibitors effectively inhibit fibrosis in different animal models; however, systemic inhibition of TGF- raises important safety issues because of the pleiotropic physiological effects of this factor. In this study, we have investigated whether topical application of P144 (a peptide inhibitor of TGF-1) ameliorates skin fibrosis in a well-characterized model of human scleroderma. C3H mice received daily subcutaneous injections of bleomycin for 4 wk, and were treated daily with either a lipogel containing P144 or control vehicle. Topical application of P144 significantly reduced skin fibrosis and soluble collagen content. Most importantly, in mice with established fibrosis, topical treatment with P144 lipogel for 2 wk significantly decreased skin fibrosis and soluble collagen content. Immunohistochemical studies in P144-treated mice revealed a remarkable suppression of connective tissue growth factor expression, fibroblast SMAD2/3 phosphorylation, and -smooth muscle actin positive myofibroblast development, whereas mast cell and mononuclear cell infiltration was not modified. These data suggest that topical application of P144, a peptide inhibitor of TGF-1, is a feasible strategy to treat pathological skin scarring and skin fibrotic diseases for which there is no specific therapy.

Keywords: antagonists, fibrosis, skin, topical administration, transforming growth factor

Abbreviations: -SMA, -smooth muscle-actin; CTGF, connective tissue growth factor; PBS, phosphate-buffered saline; TGF-, transforming growth factor-

Excessive accumulation of extracellular matrix (ECM) proteins is the hallmark of fibrotic skin conditions such as hypertrophic scarring, keloids, and localized or systemic sclerosis (scleroderma). This process is dependent on the activation of ECM synthesis in interstitial fibroblasts that often develop into -smooth muscle actin (-SMA)-positive myofibroblasts (Jimenez et al, 1996;Jelaska and Korn, 2000). One of the key molecular factors involved in both processes is transforming growth factor- (TGF-), which is consistently overexpressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts (Querfeld et al, 1999;Schiller et al, 2004). Activation of TGF- receptors leads to the activation of several kinase signaling cascades, leading to the phosphorylation of SMAD proteins as well as the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts (Shi and Massague, 2003;Daniels et al, 2004). Connective tissue growth factor (CTGF) is a soluble mediator selectively and rapidly induced in fibroblasts by the action of TGF- (Leask et al, 2004). CTGF has also been specifically detected in skin fibrotic diseases (Igarashi et al, 1996), and in animal models, it enhances and perpetuates the profibrotic effects of TGF- (Frazier et al, 1996).

Although most fibrotic diseases are usually initiated by variable degrees of inflammation, anti-inflammatory therapies are ineffective in targeting chronic fibrotic diseases that represent an important group of disorders for which there is no specific therapy. TGF- appears as an attractive target for the therapy of fibrotic diseases, and several anti-TGF- strategies have been successfully assayed in animal models of fibrosis, including several murine models of scleroderma (McCormick et al, 1999;Yamamoto et al, 1999b;Zhang et al, 2003;Lakos et al, 2004). Systemic inhibition of TGF-, however, raises important safety concerns, because this factor displays pleiotropic and potent effects in immunomodulation, inflammation, and tumor development (Akhurst, 2002). Consistently, in TGF-1-deficient mice, skin scarring is reduced but they develop a severe wasting syndrome accompanied by a generalized inflammatory response and tissue necrosis, resulting in organ failure and death (Bottinger et al, 1997). Therefore, local rather than systemic TGF- inhibition, or targeting of downstream factors involved in TGF- profibrotic signaling represent alternative strategies for the development of anti-fibrotic therapies (Daniels et al, 2004;Lakos et al, 2004). Local inhibition of TGF- has previously been attempted by the direct application of neutralizing antibodies on skin or corneal open wounds, but the application of antibodies or large peptides through the epidermal barrier appears to be an unpractical approach (Jester et al, 1997;Brahmatewari et al, 2000).

We have previously reported that the peptide P144: TSLDASIIWAMMQN, encompassing aminoacids 730–743 (accession number Q03167, SwissProt) from human TGF-1 type III receptor (-glycan), was able to block the biological activity of TGF-1 (Ezquerro et al, 2003). This peptide is derived from the membrane-proximal ligand-binding domain of -glycan (Esparza-Lopez et al, 2001), and similar to soluble -glycan (Lopez-Casillas et al, 1994), was able to interfere with TGF-1 binding to its cellular receptors on Mv1Lu cells (Ezquerro et al, 2003). P144 prevented TGF-1-dependent inhibition of Mv1Lu cell proliferation and, in cultured fibroblasts, it induced a concentration-dependent decrease on TGF-1-dependent stimulation of a reporter gene under the control of human 2(I) collagen promoter (Ezquerro et al, 2003). Intraperitoneal administration of P144 also showed potent in vivo anti-fibrotic activity in the liver of rats receiving CCl4 (Ezquerro et al, 2003). Its small size and highly lipophilic character may allow its local use by topical application in skin fibrotic diseases, thereby reducing potential systemic effects. To examine the potential anti-fibrotic effects of the topical application of this peptide in vivo, we have tested P144 on a lipogel vehicle in an animal model of skin sclerosis induced by bleomycin. This model reproduces most of the features of human scleroderma such as skin-inflammatory cell infiltration, vascular damage, mast cell activation, and prolonged skin fibrosis (Yamamoto et al, 1999c). In this model, previous studies have demonstrated that either the administration of anti-TGF- antibodies or genetic SMAD3 deficiency ameliorates fibrosis development, strongly supporting a key role for TGF- (Yamamoto et al, 1999b;Lakos et al, 2004).

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In order to study the anti-fibrotic effect of P144 (a peptide inhibitor of TGF-1) on bleomycin-induced skin fibrosis, we measured the changes induced in mice treated with bleomycin for 4 wk with and without P144 administration. It was found that bleomycin-treated mice showed a marked increase of the collagen matrix of the dermis. The dermis showed an increase of thickness that partially replaced the subcutaneous fat when compared with phosphate-buffered saline (PBS)-treated mice (Figure 1a). An increase in the collagen matrix around the upper fascia of the paniculus carnosus muscle was also observed, and it was particularly evident in Masson's trichrome-stained sections of bleomycin-treated mice skin (Figure 1b). An abundant inflammatory infiltrate, mainly composed of mononuclear cells as well as an increased number of mast cells, many of them showing degranulation features, was also observed in bleomycin-treated mice (data not shown). Mice treated with P144 anti-TGF-1 peptide showed a decrease of the dermal and hypodermal collagen area compared with vehicle-treated mice (Figure 1a, b). The thickness of the dermis was significantly decreased in P144-treated mice compared with vehicle-treated mice, which showed a thickness similar to that found in untreated mice (Figure 2). To confirm the histological observation of decreased fibrosis in P144-treated mice, we determined the pepsin-soluble collagen content of 4 mm punch skin biopsies by a colorimetric Sircol-based assay. This analysis showed a significant decrease of the soluble collagen content in P144-treated mice (Figure 2). Changes in the density of inflammatory cell infiltration, mast cell infiltration, or morphological changes of the epidermis were not observed in the P144 or vehicle-treated mice compared with those receiving only bleomycin injections (data not shown).
Citaat:
Discussion
The effectiveness of systemic strategies targeting TGF- during the development of experimental skin fibrosis has been previously demonstrated. The natural human latency-associated peptide, and neutralizing anti-TGF-1 antibodies have shown to prevent the development of skin fibrotic lesions effectively in different experimental models (McCormick et al, 1999;Yamamoto et al, 1999b;Zhang et al, 2003). These molecules are large enough to prevent its diffusion through the epidermal barrier. We have tested the feasibility of using a smaller lipophilic peptide, based on a conserved region of human type III TGF-1 receptor, as a topical therapy for skin fibrosis.

Our data consistently show that daily application of this peptide for 4 wk in parallel to fibrogenic bleomycin subcutaneous injections prevents fibrosis. Furthermore, and more importantly, regarding human skin fibrotic diseases, established fibrosis was also significantly reduced following topical application of peptide P144 for 2 wk. Improvement of established skin fibrosis in this model by post-onset therapy has been previously demonstrated with systemic interferon-, or superoxide dismutase therapy but not with systemic TGF- inhibitors (Yamamoto et al, 1999a,b,2000). We decided to test topical application of P144 because it was thought that in the case of bleomycin-induced scleroderma, this would be more efficacious than systemic administration of this peptide inhibitor. Also, in the event of P144 being toxic, topical application might reduce toxic side-effects that might be encountered following systemic administration of P144.

In previous studies in the bleomycin-induced scleroderma model, treatment with systemic anti-TGF- antibodies reduced fibrosis in parallel to a reduction in mast cell and inflammatory cell infiltration (Yamamoto et al, 1999b). The relevance of mast cells in skin fibrosis models is uncertain, because previous studies in mast cell-deficient mice have shown their dispensable contribution to fibrosis development (Everett et al, 1995;Yamamoto et al, 2001). Inflammatory cell infiltration plays an important role in the early stages of fibrosis development but its role is less clear at later stages, where it can either resolve or persist independent of the progression of fibrosis. Indeed, at later stages, fibrosis usually progresses in the absence of significant inflammatory cell infiltration. Our data and similar data using latency-associated peptide in a model of graft versus host scleroderma, or in SMAD3-deficient mice challenged with bleomycin, suggest that fibrosis can be decreased by antagonizing TGF- independent of inflammatory cell infiltration (Zhang et al, 2003;Lakos et al, 2004).

The mainstay of therapy for dermatological diseases remains topical therapy because it can readily target lesional skin decreasing systemic effects of the active principles; however, delivery of large peptides is limited by their size and physicochemical properties. We took advantage of the small size of P144 peptide and its lipophilic properties, which allowed for its application as a lipogel. Although dermal absorption of the peptide is yet to be demonstrated, our data suggest that topical application of this peptide efficiently interferes with TGF- action on dermal fibroblasts as critical players of TGF- profibrotic responses. Alternatively, its local accumulation in the epidermis could have potentially contributed to its anti-fibrotic effects. In this regard, cross-talk between the epidermis and the dermis during fibrosis development may occur, as profibrotic factors such as TGF- and monocyte chemoattractant protein 1 (MCP-1) have been detected in the epidermal layer of fibrotic skin (Galindo et al, 2001;Flanders et al, 2002). Indeed, keratinocyte overexpression of TGF-1 in transgenic mice induces dermal fibrosis (Ito et al, 2001;Yang et al, 2001;Chan et al, 2002). Interestingly, our study points to CTGF induction in skin keratinocytes of bleomycin-treated mice, which was reduced by topical anti-TGF- therapy to a higher extent than in dermal fibroblasts. Although the role of epidermal CTGF has not been established in fibrosis, previous studies demonstrate that it is expressed by normal keratinocytes in vivo (Quan et al, 2002). Also, its downregulation by ultraviolet (UV) radiation has been linked to the reduction in procollagen synthesis induced by UV radiation (Quan et al, 2002).

The demonstration of the effectiveness of topical application of a peptide inhibitor of TGF-1 provides a potentially fruitful strategy for the therapy of pathological scarring and skin fibrotic diseases. Experiments are being carried out to determine as to what extent P144 might be systemically absorbed through the skin. These experiments, together with a study of the potential toxicity of P144, will determine whether this peptide is suitable for human therapy.
http://www.nature.com/jid/journal/v1.../5603510a.html
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