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Physiology of keratinization
Oral PHYSIOLOGY
Pathology OF KERATINIZATION
N THIS brief presentation I would like t,o deal with three facets of the highl!1 will discuss (1) the conversion of complex problem of keratinization. wllular proteins into kerat,ins; (2) the disintegration of the keratinizing cell : At present, onl>a ntL (:I) the desquamwtion of the epithelial horny layers. knowledge in the field of the third fawt, tlesquamat,ion and its anomalies, (*an be applied directly to problems of oral pathology, but anomalies of dcsc~~~tt:~tion are better untlerstood if first the broader aspects are outlined.
I
Conversion of Cellular Proteins Into Keratin Fibers Polypeptide chains of most cellular proteins are tightly coiled like a ball of yarn. There is s-ray sprctropr~aphic evidence that many protein molecules have a spherical or ovoid shape. Jn contrast, to these globular proteins, the fibrous proteins. to which keratins belong, consist of more or less straightened polypeptide chains. Hair kcratins, for instance, consist, of elongat,ed molecules, about .lOO times larger in length than in width. The long asis of the polypeptitle chains has the same direction as has the macroscopic fiber. that is. the hair. 111nails, the long axes of the polyl~eptide chains are transversal. In the horny Inyet 01’ the tpidcrmis, the main clirrct,ion of the long chains is rathw irregular. In their natural statcl, t,hc krratin fibers are not maximally st,retclwd. They hare so-called alpha folds in regular intervals. Therefore, keratin fibers (‘an be st,retched into the so-~~alled beta form, a, t)otclltialit>- which is est)lnitctl in the procedures for pernlanellt wa\-ing of hair. Most cellular proteins l)eing tightly coiled, one might assume that u-hen cellular proteins tra.nsform into kerwtins this ljrocess is connected with ;I straightening of the polylwptide chains into parallel elongated molecules. Hut, as far as the epidermis is concerned, we are by no means sure that this is the cast, because the livin g epidermal cells (10 contain fibrous proteins t,o start with, the so-cnllcd tonofibrils, which hayt thr silnlc alpha-keratin spectrogratn as have the kera,tin fibws of the horny layer. IIerinpa t,ook the extreme .__ From the Section of Dermatolopy. School of Medicine. I~niversity Presented before the Eighth .\nnual Meeting of Tlrc American Patlrolo~y. Chicago, Illinois. Feb. 7, 1951. 1085
of
Chicago. .icademy
of
Oral
Slf Sir Iri>rr
One of the most importitttt changes, at least in the production of hair, is Ihe form&ion of disulfide Itridges connecting neighboring polypeptide chains (7q’ig. I). When folded chains unfold it happens tl1a.t the sulfhydryl (-ST-l ) groups of built-in cqteinc radicals on neighboring chains get sufficiently rlow The great to each other to react and undergo a so-called “oxidative closure.” resistance of keratins to I)roteolptic agettts is prima.rily due to these -S-S:-(gross bridges. Formation of these bridges is the reason that fully keratinizetl st,ructures. such as the cortex and cuticle of hair and nail plate, contain only traces of sulfhydryl groups. Most of them have undergone oxidative closure. Interestingly, just before keratinizat.ion sets in, in t,he so-called keratogettous zone, which is the region ol’ the granular layer and layers above it, there is ;I sudden increase in sulfhytlrpl content. Possibly. hitherto hidden sulfhydryl groups come to the surface hrcause of unfolding of (*hains. but, with keratinization setting in, the strong sulfhydryl reactions of the keratogenous zone disappear rather suddenly, completely or almost completely. If the keratin-
I
/
ITN
xrr
O( ’ I ITC~--CIT,--C1I,-~:II,-~‘TI~--NII,,'
(Xl ~()0(1--('lI~--('ll,---~~'TL XII
TlN I oc
(‘0 wig.
2.--s:i1t
linkagt.
A second chelnical change during kerwtinizai io11is the formatiou 01’ sillt bridges between a dicarhosylic and a diamino at4tl on t\vo neighboring chains. C’snallp the free carhosyliv groups of a glutamit ;1eitl residue :111tlthe 1’1+ee amino gronl~s of R lysine residue bewme atttxctetl to r;it~tl other by elect rostatic forces (Fig. 2). Weak alkalies or acids hrrak these salt linkages. 1I ihry :tre broken, water may penetrate in hetwcen Ihe c*ryst;lllites :mtl the fibers swrll.
A third chemical linkage contributing to the solidity of keratin moledcs is the hydrogen bond. These bonds represent attractions between it hytlrogr~n iltOlt1 and an electronegative atom, usually oxygen. There is strong hydrogen lmntling in kerat,ins, both in the main chains with their all~ha folds ( P’ig. 3 i and in between the chains. The knowledge that h-drogen l)onds contribute to the solidity of keratins has led to some l)rartit~;rI appliwtion. Alexander tlemonstratecl that when hair is ttwtctl with wncrntrntecl lithium l)romi;lc solutions there is :I revcrsit~lc l)reak OF hyclrogctl 1~01~~1s ant1 the Irlolecltlill l3slwittlcnts in iny laboratory restrnct,nre of the hair krrzttins is loosn~etl. \-~n.led th:lt by lithium l~romicle treatmetlt hair call IJCtllatle so permeal)le thilt ~~inyworm fungi insitle the hair can he killed easily a I’ter such treatment. IYe illSO ol~tainrcl some encouraging results in t watnlenl of fungus in fedions ill the nails by using strong lithium bromide solutions.
10X8
STEPHEN t_
ROTHMAN
I Gsulfide bridging is c*atalyzctl hy cduppet-. It’ sheep are f’etl ii cwl)pet*tlefic~ient diet the wool is oI’ l)oot. quality. 1larstott showrtl that irt such wc~~l t’he keratogenous zone is trtt titttfis longer th;ttt IIOITM~. ;ttttI the tlisulfitltb closu~~t~ is delayed Kay several days. l’hi.s efiec~i oI’ c’ol)pc’t’ is sl)pcitic. It mttttot lw (‘oI)ltc~t’ substituted by cobalt, by other h~;t\-y tttetals, 01’ by oxitlative ~nzytttes. is t,he only agent. we kttow Ol' to tlirectl~~ itrflttettcde thr I)rocess of keratittixatiott. AilI other biologic agents which ttrotlify kct,;ltitriz,atiott. such as vitamin A or Mrogenic hormone. tttotlify the potenMities 01 gt~rtttittatirr ~~pifheliai wlls I)y tnctaplasia and thetaeby ittflltt’ttct’ thtt pt.odu($iott 01’ k~ritt,itl in~litw:tly, I)111 (~pl)er acts most directly ott tltra c~ornii’yitrg cell ;~t thth tttourrttt 01 c.c,t.ttitic.:liicltt. ln thtlir over-all chernic~al caotnpositiott, ktlratins differ from other l)t’otc1irts IJ.V iheir high sulfur c*orttettt. ()I’ tv)ntw, the high sttlt’ur c~onlrni c*;tttttc)i I)(& cvla.inrd by the ilisulfitlc closure. Iwausc this ~~IOSII~Y~ ~1~s tlot c~h:ttrg~~thta absdutc or relative amount or sulfur. The only possible csplanation I (‘at1 MY’ is that amino acids whic:h (10 trot (‘ottfain sulfltr are split OR frottt thta kerittittizing protein. This assutttptiott is suplmrted by findings thal keratinixrd st,rttc+tuWS (10 contaitt il gl’eilt tltltlltWl~ itIt< tilt’~C’ iIltlOlllltS Of 1’Wt amino acids IJtli t1Olli Or the Sulfur-~OIltititlitl~ antino ads. tuet~hiottitw. cgsteinc, anal cyst itIc%. ()f course, if 0dy7 amino ;t4tIs which do not c~ontain sulfur arc split of’, 111~8 percentage (*ontent of sulfur will iticrrast~. ‘l’here is accumulation of giycogen in t,he keratogenous zotte. This The rnrrgp Iiberit t catI giycAogett disappears wit,h the onset, of keratinization. I)p the glycogenolysis is thought to be utilized for the disulfide closure.
Disintegration
of the Keratinizing
Cell
Keratinizing cells lose considerable amounts of water. While the living wlls which a,re going to kera.tinize contain an average of 70 per cent water. keratinized &u&ares contain only about. 10 per cent, water. In 1929 I pointed ottt that probably this water is losb to the outside. 1-n ot,her words, one part of the insensible water loss from the skin surfart) may originate from I ht keratinization process. Esl)criments in my laltorat~ory have supported this view. While in acute infl;ttrtrtr;ttot*y proresses the insensible water loss is otrly slightI>- increased. it’ at all. it is augntentetl two IO three times the nomal values during the postinflanltnn.tot~y desyuamation because the keratin protluc~tion is now accelerated. Whenever it pathologic Ijrocess causes acceleratetl keratinization, as is the cast in psoriasis and rxfoliative dermatitis. The ittdermatitis we fount1 sensible water loss is markedly increased. Tn exfoliative tenfold increased values of water loss, This is the reason that patients suffering from exfoliative dertttittit is Ita\:e continuous chills anal clrink excessive itmounts of water without ittc+t.c:tsing thei t* urirta,r*y vcrlunte. Cytoplasmic cotnI)onetlts ;II’(’ split and clecotttl)osed during ket~al~ittiz;~tion. Tlipids are lihera.tetl from Iipc)l)t~rtteins itttd al)l)e;lr Ott the surface. There is cvidenee tha.t the cttolestt~rol of the skin surface film stems mainly front keratinizing cells and not, from the sebaceous glands. We were able t,o follovr the decomposition of phospholipids during the keratinization process and
found that after choline has beet1 split off I’rom the ~thospholipjd t~olecnl~~. choline itself is also decomposed. TloweverJ if keratinization is jncotttplrte. as is the case in parakeratotic: proresses: relatively little choline is C~WO~JI-posed. The breakdown of the ~11 nucleus brings about, liberation of pt~tttos;tls :~tt(l purines which (aan be recovered from hair estracets and front the skin SI~I’t’il(‘?.
Desquamation and Its Anomalies has IJW~ said so far about keratittizalion intlivatrs that this is ttoi ;I Cltliltttitati\‘ely uniform process, but differs in tlrgl*ef~ accv)rtling to the Iliitlll~~~ of’ the germinative epitheliuttt. If 011etakes the tlisnlfide ~10sure as it ttteasnt’e of the completeness of keratinization, one cittt say that in the tlrvelopment 01 hair cortex and cuticle the keratjittization is relatively tttost complrte w&h hard keratin structures resulting. The keratinization of the epidermis is relativeI!, incomplete and the resulting kcratjtt is soft. In (*(tntr;lst, to hard keratirt structures which may grow itttlrfittitrly, soft keratins sIe:tdil~ ;lesytlamiItr itr itivisihle sm;ill ~~articlrs. F’orrttation of visible scitles OII the skitt sttrt’;t(ae is itln-ays tt;tthologie. It is based on two different Itathottte~hanistiis. In nttt’ C’ilW sealing is ~~rcsrrit because there is increasetl cellular proliferation itttd this lea(ls to accaelrration as is the (*itse in Itsoriasis atttl esl’oliati\r and increase of horn protluctiott, dermatitis. The keratinizatiott is It;tthologic;llly incvmplete ; IILI~*IP~~ frilgntents are retained. sulfhydryl content. choline eontettt,. etca. 01: t,he scales is high, and the lamellae are not broken down to invisible particles. In the second ease, for examltle, in ichthyosis. there is a thickening of the cvltnpavt horny layer because the desquamation is retarded. There is an anomaly of separation. On the surface the layer breaks or tears so that lntnellat~ form. Tn this second form of faulty desquamation there is no acceleration of epithelial ~11 proliferation or of keratin formation, no increase in loss of water vapcjr. attd there are no signs of incoml)lete keratinization sttcah as parakeratosis. l’roh~~hl~ the most clinically significant anomaly of desquarnation is the inhibition of’ the physiologic peeling. Irndcr the influenvc of it Et-eat. y:tt*iet)’ 01’ stitrtnli it may happen that, ihe epidermis, ittsteittl of forming ;I sot’1 desquamatinp keratin, protluc~es a hartler variety lvhiczh does not tles(~tl;tttt;tt<~. This harder epidermal keratin represents the produd of ;I more c~ompl~t( keratinization process reminiscent of that of hair. The most characteristic examples of’ this attotttal~ it t’c cotns antI c~allttst~s. in which an extremely thick and hard horny layer l)iles 111~antler the influency Of prcssuw. TO a fitter deplarcJ, the Sil?TlP ~lIlOlllill~ cat1 t)e observed iti response bliescher to practiea1ly all mild, banal, external physical and vhetnical injuries. was the tirst to observe ant1 to measure this reaction. IT? sltowed thilt iti response to ultraviolet irradiation ihe horny lityt’r thickens and that this thickening contributes to Ihe protection against the damaging effect of further irradiat,ion. It’ was found in our laboratory fhat mild rubbittp has the sattte effect. In our experiments, massage of the same skin area for ten minutes \Vhitt
Pathology OF KERATINIZATION
N THIS brief presentation I would like t,o deal with three facets of the highl!1 will discuss (1) the conversion of complex problem of keratinization. wllular proteins into kerat,ins; (2) the disintegration of the keratinizing cell : At present, onl>a ntL (:I) the desquamwtion of the epithelial horny layers. knowledge in the field of the third fawt, tlesquamat,ion and its anomalies, (*an be applied directly to problems of oral pathology, but anomalies of dcsc~~~tt:~tion are better untlerstood if first the broader aspects are outlined.
I
Conversion of Cellular Proteins Into Keratin Fibers Polypeptide chains of most cellular proteins are tightly coiled like a ball of yarn. There is s-ray sprctropr~aphic evidence that many protein molecules have a spherical or ovoid shape. Jn contrast, to these globular proteins, the fibrous proteins. to which keratins belong, consist of more or less straightened polypeptide chains. Hair kcratins, for instance, consist, of elongat,ed molecules, about .lOO times larger in length than in width. The long asis of the polypeptitle chains has the same direction as has the macroscopic fiber. that is. the hair. 111nails, the long axes of the polyl~eptide chains are transversal. In the horny Inyet 01’ the tpidcrmis, the main clirrct,ion of the long chains is rathw irregular. In their natural statcl, t,hc krratin fibers are not maximally st,retclwd. They hare so-called alpha folds in regular intervals. Therefore, keratin fibers (‘an be st,retched into the so-~~alled beta form, a, t)otclltialit>- which is est)lnitctl in the procedures for pernlanellt wa\-ing of hair. Most cellular proteins l)eing tightly coiled, one might assume that u-hen cellular proteins tra.nsform into kerwtins this ljrocess is connected with ;I straightening of the polylwptide chains into parallel elongated molecules. Hut, as far as the epidermis is concerned, we are by no means sure that this is the cast, because the livin g epidermal cells (10 contain fibrous proteins t,o start with, the so-cnllcd tonofibrils, which hayt thr silnlc alpha-keratin spectrogratn as have the kera,tin fibws of the horny layer. IIerinpa t,ook the extreme .__ From the Section of Dermatolopy. School of Medicine. I~niversity Presented before the Eighth .\nnual Meeting of Tlrc American Patlrolo~y. Chicago, Illinois. Feb. 7, 1951. 1085
of
Chicago. .icademy
of
Oral
Slf Sir Iri>rr
One of the most importitttt changes, at least in the production of hair, is Ihe form&ion of disulfide Itridges connecting neighboring polypeptide chains (7q’ig. I). When folded chains unfold it happens tl1a.t the sulfhydryl (-ST-l ) groups of built-in cqteinc radicals on neighboring chains get sufficiently rlow The great to each other to react and undergo a so-called “oxidative closure.” resistance of keratins to I)roteolptic agettts is prima.rily due to these -S-S:-(gross bridges. Formation of these bridges is the reason that fully keratinizetl st,ructures. such as the cortex and cuticle of hair and nail plate, contain only traces of sulfhydryl groups. Most of them have undergone oxidative closure. Interestingly, just before keratinizat.ion sets in, in t,he so-called keratogettous zone, which is the region ol’ the granular layer and layers above it, there is ;I sudden increase in sulfhytlrpl content. Possibly. hitherto hidden sulfhydryl groups come to the surface hrcause of unfolding of (*hains. but, with keratinization setting in, the strong sulfhydryl reactions of the keratogenous zone disappear rather suddenly, completely or almost completely. If the keratin-
I
/
ITN
xrr
O( ’ I ITC~--CIT,--C1I,-~:II,-~‘TI~--NII,,'
(Xl ~()0(1--('lI~--('ll,---~~'TL XII
TlN I oc
(‘0 wig.
2.--s:i1t
linkagt.
A second chelnical change during kerwtinizai io11is the formatiou 01’ sillt bridges between a dicarhosylic and a diamino at4tl on t\vo neighboring chains. C’snallp the free carhosyliv groups of a glutamit ;1eitl residue :111tlthe 1’1+ee amino gronl~s of R lysine residue bewme atttxctetl to r;it~tl other by elect rostatic forces (Fig. 2). Weak alkalies or acids hrrak these salt linkages. 1I ihry :tre broken, water may penetrate in hetwcen Ihe c*ryst;lllites :mtl the fibers swrll.
A third chemical linkage contributing to the solidity of keratin moledcs is the hydrogen bond. These bonds represent attractions between it hytlrogr~n iltOlt1 and an electronegative atom, usually oxygen. There is strong hydrogen lmntling in kerat,ins, both in the main chains with their all~ha folds ( P’ig. 3 i and in between the chains. The knowledge that h-drogen l)onds contribute to the solidity of keratins has led to some l)rartit~;rI appliwtion. Alexander tlemonstratecl that when hair is ttwtctl with wncrntrntecl lithium l)romi;lc solutions there is :I revcrsit~lc l)reak OF hyclrogctl 1~01~~1s ant1 the Irlolecltlill l3slwittlcnts in iny laboratory restrnct,nre of the hair krrzttins is loosn~etl. \-~n.led th:lt by lithium l~romicle treatmetlt hair call IJCtllatle so permeal)le thilt ~~inyworm fungi insitle the hair can he killed easily a I’ter such treatment. IYe illSO ol~tainrcl some encouraging results in t watnlenl of fungus in fedions ill the nails by using strong lithium bromide solutions.
10X8
STEPHEN t_
ROTHMAN
I Gsulfide bridging is c*atalyzctl hy cduppet-. It’ sheep are f’etl ii cwl)pet*tlefic~ient diet the wool is oI’ l)oot. quality. 1larstott showrtl that irt such wc~~l t’he keratogenous zone is trtt titttfis longer th;ttt IIOITM~. ;ttttI the tlisulfitltb closu~~t~ is delayed Kay several days. l’hi.s efiec~i oI’ c’ol)pc’t’ is sl)pcitic. It mttttot lw (‘oI)ltc~t’ substituted by cobalt, by other h~;t\-y tttetals, 01’ by oxitlative ~nzytttes. is t,he only agent. we kttow Ol' to tlirectl~~ itrflttettcde thr I)rocess of keratittixatiott. AilI other biologic agents which ttrotlify kct,;ltitriz,atiott. such as vitamin A or Mrogenic hormone. tttotlify the potenMities 01 gt~rtttittatirr ~~pifheliai wlls I)y tnctaplasia and thetaeby ittflltt’ttct’ thtt pt.odu($iott 01’ k~ritt,itl in~litw:tly, I)111 (~pl)er acts most directly ott tltra c~ornii’yitrg cell ;~t thth tttourrttt 01 c.c,t.ttitic.:liicltt. ln thtlir over-all chernic~al caotnpositiott, ktlratins differ from other l)t’otc1irts IJ.V iheir high sulfur c*orttettt. ()I’ tv)ntw, the high sttlt’ur c~onlrni c*;tttttc)i I)(& cvla.inrd by the ilisulfitlc closure. Iwausc this ~~IOSII~Y~ ~1~s tlot c~h:ttrg~~thta absdutc or relative amount or sulfur. The only possible csplanation I (‘at1 MY’ is that amino acids whic:h (10 trot (‘ottfain sulfltr are split OR frottt thta kerittittizing protein. This assutttptiott is suplmrted by findings thal keratinixrd st,rttc+tuWS (10 contaitt il gl’eilt tltltlltWl~ itIt< tilt’~C’ iIltlOlllltS Of 1’Wt amino acids IJtli t1Olli Or the Sulfur-~OIltititlitl~ antino ads. tuet~hiottitw. cgsteinc, anal cyst itIc%. ()f course, if 0dy7 amino ;t4tIs which do not c~ontain sulfur arc split of’, 111~8 percentage (*ontent of sulfur will iticrrast~. ‘l’here is accumulation of giycogen in t,he keratogenous zotte. This The rnrrgp Iiberit t catI giycAogett disappears wit,h the onset, of keratinization. I)p the glycogenolysis is thought to be utilized for the disulfide closure.
Disintegration
of the Keratinizing
Cell
Keratinizing cells lose considerable amounts of water. While the living wlls which a,re going to kera.tinize contain an average of 70 per cent water. keratinized &u&ares contain only about. 10 per cent, water. In 1929 I pointed ottt that probably this water is losb to the outside. 1-n ot,her words, one part of the insensible water loss from the skin surfart) may originate from I ht keratinization process. Esl)criments in my laltorat~ory have supported this view. While in acute infl;ttrtrtr;ttot*y proresses the insensible water loss is otrly slightI>- increased. it’ at all. it is augntentetl two IO three times the nomal values during the postinflanltnn.tot~y desyuamation because the keratin protluc~tion is now accelerated. Whenever it pathologic Ijrocess causes acceleratetl keratinization, as is the cast in psoriasis and rxfoliative dermatitis. The ittdermatitis we fount1 sensible water loss is markedly increased. Tn exfoliative tenfold increased values of water loss, This is the reason that patients suffering from exfoliative dertttittit is Ita\:e continuous chills anal clrink excessive itmounts of water without ittc+t.c:tsing thei t* urirta,r*y vcrlunte. Cytoplasmic cotnI)onetlts ;II’(’ split and clecotttl)osed during ket~al~ittiz;~tion. Tlipids are lihera.tetl from Iipc)l)t~rtteins itttd al)l)e;lr Ott the surface. There is cvidenee tha.t the cttolestt~rol of the skin surface film stems mainly front keratinizing cells and not, from the sebaceous glands. We were able t,o follovr the decomposition of phospholipids during the keratinization process and
found that after choline has beet1 split off I’rom the ~thospholipjd t~olecnl~~. choline itself is also decomposed. TloweverJ if keratinization is jncotttplrte. as is the case in parakeratotic: proresses: relatively little choline is C~WO~JI-posed. The breakdown of the ~11 nucleus brings about, liberation of pt~tttos;tls :~tt(l purines which (aan be recovered from hair estracets and front the skin SI~I’t’il(‘?.
Desquamation and Its Anomalies has IJW~ said so far about keratittizalion intlivatrs that this is ttoi ;I Cltliltttitati\‘ely uniform process, but differs in tlrgl*ef~ accv)rtling to the Iliitlll~~~ of’ the germinative epitheliuttt. If 011etakes the tlisnlfide ~10sure as it ttteasnt’e of the completeness of keratinization, one cittt say that in the tlrvelopment 01 hair cortex and cuticle the keratjittization is relatively tttost complrte w&h hard keratin structures resulting. The keratinization of the epidermis is relativeI!, incomplete and the resulting kcratjtt is soft. In (*(tntr;lst, to hard keratirt structures which may grow itttlrfittitrly, soft keratins sIe:tdil~ ;lesytlamiItr itr itivisihle sm;ill ~~articlrs. F’orrttation of visible scitles OII the skitt sttrt’;t(ae is itln-ays tt;tthologie. It is based on two different Itathottte~hanistiis. In nttt’ C’ilW sealing is ~~rcsrrit because there is increasetl cellular proliferation itttd this lea(ls to accaelrration as is the (*itse in Itsoriasis atttl esl’oliati\r and increase of horn protluctiott, dermatitis. The keratinizatiott is It;tthologic;llly incvmplete ; IILI~*IP~~ frilgntents are retained. sulfhydryl content. choline eontettt,. etca. 01: t,he scales is high, and the lamellae are not broken down to invisible particles. In the second ease, for examltle, in ichthyosis. there is a thickening of the cvltnpavt horny layer because the desquamation is retarded. There is an anomaly of separation. On the surface the layer breaks or tears so that lntnellat~ form. Tn this second form of faulty desquamation there is no acceleration of epithelial ~11 proliferation or of keratin formation, no increase in loss of water vapcjr. attd there are no signs of incoml)lete keratinization sttcah as parakeratosis. l’roh~~hl~ the most clinically significant anomaly of desquarnation is the inhibition of’ the physiologic peeling. Irndcr the influenvc of it Et-eat. y:tt*iet)’ 01’ stitrtnli it may happen that, ihe epidermis, ittsteittl of forming ;I sot’1 desquamatinp keratin, protluc~es a hartler variety lvhiczh does not tles(~tl;tttt;tt<~. This harder epidermal keratin represents the produd of ;I more c~ompl~t( keratinization process reminiscent of that of hair. The most characteristic examples of’ this attotttal~ it t’c cotns antI c~allttst~s. in which an extremely thick and hard horny layer l)iles 111~antler the influency Of prcssuw. TO a fitter deplarcJ, the Sil?TlP ~lIlOlllill~ cat1 t)e observed iti response bliescher to practiea1ly all mild, banal, external physical and vhetnical injuries. was the tirst to observe ant1 to measure this reaction. IT? sltowed thilt iti response to ultraviolet irradiation ihe horny lityt’r thickens and that this thickening contributes to Ihe protection against the damaging effect of further irradiat,ion. It’ was found in our laboratory fhat mild rubbittp has the sattte effect. In our experiments, massage of the same skin area for ten minutes \Vhitt