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2 The Extracellular Matrix: Composition and Architecture in Young, Healthy Skin

2 The Extracellular Matrix: Composition and Architecture in Young, Healthy Skin

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5 Skin Extracellular Matrix and Environmental Exposure



103



least one sequence of repeating Glycine-X-Y residues where the X and Y are

typically proline and hydroxyproline respectively (Ramshaw et al. 1998). Collagen

monomers are, in turn, assembled from three alpha chains in which the aligned

Gly-X-Y repeats form a triple helical domain that is stabilised by the hydroxylation

of proline (Birk and Bruckner 2005). The major structural fibrillar collagens such as

collagen I, II and III are composed of an uninterrupted helical region which

comprises the entire molecule in the processed form. Other sub-families such as the

FACIT collagens (Fibril Associated with Interrupted Triple Helices) and the network forming collagens (e.g. collagen IV, VI and VIII) contain discontinuous triple

helical regions and/or substantial non-helical (globular) domains. Although some

collagens (e.g. collagen II in cartilage) are confined to specific tissues, many collagens are ubiquitously expressed.

The most abundant collagens found in the skin are the interstitial fibrillar collagens,

types I, III and V. These collagens form fibrils which range in diameter from 80 to

180 nm (ovine skin) and which are commonly arranged into large fibril bundles

throughout the dermis (Fang et al. 2012). The most abundant non-fibrillar collagen in

skin and in many other tissues is collagen VI. The beaded microfibrillar networks

formed by this collagen encircles dermal collagen I fibrils and are thought to play a

role in mediating matrix assembly and fibroblast phenotype (Sabatelli et al. 2011;

Theocharidis et al. 2015). Other dermal collagens exhibit more localised distributions.

Collagen IV for example, assembles into a sheet structure that forms the basal

lamina. Collagen XVII stabilises basement membranes including the dermal epidermal junction (DEJ) by assembling into hemi desmosomes that anchor the epidermis to

the dermis. Similarly, collagen VII anchors the dermis to the DEJ (Abreu-Velez and

Howard 2012; Chanut-Delalande et al. 2004; Craven et al. 1997; Loffek et al. 2014).



5.2.2



Proteoglycans and Glycosaminoglycans



Proteoglycans are proteins that are heavily modified by glycosaminoglycan (GAG)

side chains with the exception of hyaluronic acid (HA) which does not contain a

protein core. The most abundant proteoglycan in skin is decorin, a member of the

small leucine rich proteoglycan family (SLRPs) which is modified with a single

GAG chain. It regulates the early stages of collagen fibril formation adorning the

length of mature collagen fibrils, protecting them against proteolysis (Ruehland

et al. 2007; Stuart et al. 2011; Yamaguchi et al. 1990). Other proteoglycans present

in skin include versican, a constituent of blood vessels in the dermis, perlecan

which is localised to the basement membrane, cell-surface expressed glypians and

syndecans, and HA which is localised to the epidermis (Maquart and Monboisse

2014; Papakonstantinou et al. 2012; Wang et al. 2007). The GAG chains on HA

readily bind water molecules to help maintain stratum corneum hydration and

barrier function. HA is also an important molecule for wound healing and fibroblast

migration (Papakonstantinou et al. 2012). The age-related decrease in epidermal

localised HA is thought to contribute towards skin dehydration and loss of skin



104



K.T. Mellody et al.



elasticity. The use of HA fillers injected into the skin not only decreases the clinical

appearance of wrinkles but also restores dermal matrix components by stimulating

de novo collagen synthesis (Wang et al. 2007).



5.2.3



Elastic Fibres



The mature elastic fibre system is a multi-component assembly that includes fibrillin microfibrils and elastin fibres that endow dynamic tissues such as skin, with

passive elastic recoil and resilience (Baldwin et al. 2013). In the papillary dermis,

‘candelabra-like’ structures, consisting primarily of fibrillin microfibrils, intercalate

with the DEJ. Deeper in the reticular dermis, these fibrillin microfibrils form an

outer mantle around a highly cross-linked elastin core that together forms the

mature elastic fibre system (Kielty et al. 2002; Sakai et al. 1986).

Elastin is a multi-domain, highly hydrophilic protein which is encoded by a

single gene on chromosome 7q11.23. Elastogenic cells, such as fibroblasts within

the skin, secrete the soluble precursor, tropoelastin, which is subsequently processed (by the amine oxidase: lysyl oxidase [LOX]) to the cross-linked, insoluble

mature fibre (Lucero and Kagan 2006). Functionally, the N-terminus of elastin

endows the protein with its elastic recoil whilst the C-terminus and a recently

identified central region of the protein are actively involved in aVb3 and aVb5

integrin-mediated cell adhesion and signalling respectively (Bax et al. 2009; Lee

et al. 2014). Importantly however, elastic fibre assembly does not occur in isolation

but is dependent on the presence of fibrillin microfibrils.

Fibrillins are large glycoproteins (*340 kDa) that are encoded by three separate

genes (FBN 1-3) on distinct chromosomes. Fibrillin-1, which is the most abundant

isoform in adult tissues, forms the major component of the insoluble fibrillin-rich

microfibrils localised within the dermis. Fibrillins-2 and -3 are typically expressed in

early development, although fibrillin-2 is also expressed by keratinocytes and is present

at low levels within the DEJ in adult tissue (Brinckmann et al. 2010; Haynes et al. 1997).

The fibrillins are composed mainly of repeating calcium binding epidermal growth

factor-like (cbEGF) domains. Fibrillin monomers polymerise to form insoluble

fibrillin-rich microfibrils that exhibit a characteristic ‘beads on a string’ appearance with

a regular inter-bead periodicity of *56 nm. Microfibril assembly occurs pericellularly

and is dependent upon integrin binding, fibronectin, heparin and heparin sulphate (Bax

et al. 2003; Kinsey et al. 2008; Massam-Wu et al. 2010; Sabatier et al. 2014).

In addition to acting as a molecular scaffold for tropoelastin deposition in elastogenesis, coacervation studies have further highlighted the importance of fibrillin in

anchoring and directing the alignment of tropoelastin molecules prior to

cross-linking (Clarke et al. 2005). Further, the interaction of microfibrils with cells

and the latent transforming growth factor beta (TGFb) growth factor binding proteins

(LTBP) and the Latency associated peptide (LAP) complex suggest fibrillin

microfibrils also may orchestrate elastogenesis by regulating TGFb availability

within the ECM space (Kaartinen and Warburton 2003; Massam-Wu et al. 2010).



5 Skin Extracellular Matrix and Environmental Exposure



105



Aberrant TGFb signalling and disruption to elastic fibres assembly during prenatal

and neonatal development is a hallmark of Marfan syndrome (MFS) caused by

mutations in the fibrillin-1 gene (Gigante et al. 1999; Neptune et al. 2003). However,

it is not clear if microfibrils also regulate elastic fibre assembly in adult tissue or if

their composition changes as part of the ageing process. This is why our laboratory is

focussed on understanding how photodamaged fibrillin microfibrils affect the mature

elastic fibre system in skin and if their composition changes in ageing. Interestingly,

although fibrillin microfibrils play an important role in determining tissue function

and maintaining homeostasis they constitute only relatively a small proportion of the

organic material within the dermis.



5.2.4



The Importance of “Minor” Components



The “major” components of the dermal ECM, in terms of their relative abundance,

are important in maintaining normal skin function. As a consequence, attention has

focussed almost exclusively on widely expressed proteins, such as collagen I and to

a lesser extent elastin, and on the GAG chain of HA as key biomarkers of damage

and targets for repair. However, there is compelling evidence that less abundant and

hence “minor” ECM components play central roles in mediating the architecture of

large ECM assemblies and in controlling cell-mediated tissue homeostasis. In the

case of fibrillar collagens, for example, the SLRP decorin controls collagen fibril

diameter and packing. The importance of this supra-molecular architecture to

maintaining skin function is evident in the decorin knockout mouse which suffers

from increased skin fragility (Danielson et al. 1997). However, decorin is not the

only mediator of collagen fibril structure. Other fibril associated SLRPs such as

biglycan, fibromodulin, versican, collagens (XII and XVI) and the ECM glycoprotein periostin may be equally important in maintaining tissue structure (Grassel

and Bauer 2013; Maruhashi et al. 2010). In addition to its structural role, decorin, in

common with elastic fibre associated fibrillin microfibrils, is a negative regulator of

TGFb (Stuart et al. 2011; Yamaguchi et al. 1990).

As discussed previously, fibrillin microfibrils sequester and therefore play a role in

regulating the availability of TGFb within the ECM (Massam-Wu et al. 2010).

Fibrillin-1 mutations that cause MFS can alter protein structure and function, rendering the molecule susceptible to proteolysis and perturbing TGFb signalling

(Habashi et al. 2006; Kirschner et al. 2011; Mellody et al. 2006). A central region of

the fibrillin-1 gene, often referred to as the neonatal region (exons 24-32), is prone to

a cluster of mutations that result in an early lethal form of MFS which is associated

with profound skin wrinkling (Tiecke et al. 2001). Tables 5.1 and 5.2 summarise the

molecular interactions and potential function of both “major” and “minor” dermal

components which play important roles in modifying cell behaviour, regulating

matrix-to-matrix interactions and inducing protease expression. The abundant fibrillar collagens endow the skin with tensile strength and together with the minor

collagens also regulate many other cellular and extracellular processes such as cell



106



K.T. Mellody et al.



Table 5.1 Dermal extracellular matrix proteins

Crosslink

susceptibility

(% 1° sequence)



Major component



Structure



Functions and

interactions



ROS/UVR

susceptibility

(% 1° sequence)



Fibrillar

collagens



I



Forms fibrils



4.20



8.91



III



Forms fibrils



5.47



8.39



V



Forms fibrils



4.89



9.27



VII



Forms fibrils



4.17



10.55



IV



Forms sheet

structure



5.95



8.55



XVII



Transmembrane

protein



7.28



8.55



VI



Forms beaded

microfilaments



7.40



11.58



XII



Associates with

collagen fibrils



Provides tensile

strength and

rigidity. Involved

in fibroblast

migration

Important in skin

development and

collagen I

fibrillogenesis

Predominant at the

core of fibril

bundles. Provides

a scaffold for

collagen I

fibrillogenesis

Major component

of the basement

membrane.

Anchors the

epidermis to the

dermis

Adhesion

molecule within

the DEJ. Provides

a scaffold for ECM

molecules

Component of

hemidesmosomes.

Essential for

organisation of the

basement

membrane and

directs

keratinocyte

migration in

wound healing

Regulates cellular

functions and

provides structural

support to cells

Regulates the

organisation and

mechanical

properties of

collagen fibril

bundles



7.86



10.23



Non-fibrillar

collagens



(continued)



5 Skin Extracellular Matrix and Environmental Exposure



107



Table 5.1 (continued)

Major component



Structure



XIII



Functions and

interactions



ROS/UVR

susceptibility

(% 1° sequence)



Crosslink

susceptibility

(% 1° sequence)



Involved in

angiogenesis



5.16



11.30



8.26

8.82

Induces skin

fibroblast

quiescence and

differentiation

XVI Associates with

Component of

5.81

9.48

microfibrils

hemidesmosomes

and induces

metalloproteinase

expression. May

be a fibrillin-1

microfibril

component within

the papillary

dermis

10.69

XXII

Component of the 4.63

hair follicle

basement

membrane and

interacts with cell

surface integrins

Human skin collagens. Fibrillar and non-fibrillar collagens are major components of the ECM in skin.

Collagens not only provide structural support to skin but are also involved in a wide-range of molecular

interactions as shown. Primary sequence analyses of the collagens predict that they are protected against

UV and ROS-induced damage but are susceptible to crosslinking

XIV



Associates with

collagen fibrils



migration (collagen I) (Li et al. 2004), angiogenesis (collagen XVIII) (Zatterstrom

et al. 2000) and metalloproteinase expression (collagen XVI) (Bedal et al. 2014)

(Table 5.1). Equally important are the non-collagenous proteins, many present in low

abundance, which also exhibit a wide range of molecular interactions from collagen

fibrillogenesis (decorin and biglycan) (Bielefeld et al. 2011; Zhang et al. 2009),

wound healing (fibronectin) (Bielefeld et al. 2011) to cytokine regulation (fibrillin),

thus highlighting the dynamic nature of the ECM (Table 5.2). Whilst the dermis is

enriched in structural ECM proteins (in particular fibrillar collagens and elastin),

ECM proteins are also found in both the hypodermis and epidermis.



5.2.5



Non-dermal Extracellular Matrix Proteins



We have previously shown that two LTBP isoforms and the ECM cross-linking

lysyl oxidase-like enzyme (LOXL-1) are expressed in the human epidermis

(Langton et al. 2012). This enzyme is also expressed epidermally in the mouse and

there is little evidence in the literature of expression in the dermis (Liu et al. 2004).



Binds to integrins and is essential

for wound healing. Regulates

fibrillin assembly



Supermolecular fibres



Associates with

microfibrils



Heparan sulphate

proteoglycan



Large chondroitin

sulphate proteoglycan



Large chondroitin

sulphate proteoglycan



Perlecan



Aggrecan



Versican



Fibronectin



Fibulins



PGs



Involved in hair follicle formation

and cell migration, adhesion,

proliferation and signalling



Interacts with fibulin-1 and is

involved in the dermal wound

healing response



Basement membrane associated

PG involved in angiogenesis.

Bridges laminin and collagen IV

networks



Cell-signalling and important in

elastogenesis. Crosslinks

tropoelastin to LOX



Regulates TGFb bioavailability.

Binds fibrillin-rich microfibrils

and influences cell function



Regulate TGFb and bind elastin



Forms microfibrils



Large latent complex



LTBPs



Secreted as soluble precursor,

tropoelastin. Provides elastic

recoil and regulates cell signalling



Forms elastic fibres



Elastin



Fibrillins



Functions and interactions



Structure



Major component



Table 5.2 Non-collagenous proteins in human skin



(continued)



7.38



8.47



7.46



13.78



4.42



7.66



21.06



7.09



8.45



13.08



8.00

8.66



24.81



5.92



Crosslink

susceptibility

(% 1° sequence)



19.39



2.50



ROS/UVR

susceptibility

(% 1° sequence)



108

K.T. Mellody et al.



Cell-matrix interactions and

modulates collagen fibrillogenesis

and elastin fibre assembly



Tenascin X



9.13



9.53



13.54



11.57



9.95



17.62



8.43



11.46



11.75



18.67



11.37



Crosslink

susceptibility

(% 1° sequence)



9.04



ROS/UVR

susceptibility

(% 1° sequence)



Many of the non-collagenous molecules are present in low abundance but are important in maintaining tissue integrity in skin. They, like the collagenous molecules, are implicated

in many biological processes that highlight the dynamic nature of the ECM. Primary sequence analyses of these molecules predict them to be more susceptible to UV and

ROS-induced damage compared with collagens



Anti-adhesion molecule.

Expressed in tissue injury and

stimulates fibronectin mediated

cell-migration



Tenascin C



Associates with fibrillin-rich

microfibrils and modifies their

function. Binds active TGFb and

is involved in thermoregulation



Associated with fibrillin

microfibrils



MAGP1

(Microfibrillar-associated

prot. 2)



Cell signalling molecule which

interacts with TGFb and

BMP. Involved in collagen

fibrillogenesis

Involved in the covalent

crosslinking of collagen and

elastin in the ECM. May regulate

gene transcription



Chondroitin/dermatan

sulphate proteoglycan



Biglycan



Collagen fibrillogenesis,

protection from proteolysis.

Inter-molecular bridges.

Negatively regulates TGFb

signalling and modulates cell

adhesion



Copper and quinone

dependent enzymes



Chondroitin/dermatan

sulphate proteoglycan



Decorin



SLRPs



Functions and interactions



Lysyl oxidase family of

proteins



Structure



Major component



Table 5.2 (continued)



5 Skin Extracellular Matrix and Environmental Exposure

109



110



K.T. Mellody et al.



The role played by these proteins in the epidermis is unclear: although LTBPs

commonly associate with fibrillin microfibrils and LOX enzymes contribute to

elastic fibre assembly the epidermis itself is devoid of mature elastic fibres. The

location of these proteins in basal keratinocytes suggests that epidermal cells may

synthesise key proteins in the papillary dermis. The final layer of the skin, the

hypodermis, is comprised primarily of white adipose tissue containing

pre-adipocytes, adipocytes, macrophages and fibroblasts. The ECM content of this

layer is sparse and the UVR exposure is likely to be low (Askew 2002). However, it

is now becoming clear that the hypodermis is susceptible to longer wavelength

UVR, becoming thinner in photoexposed regions of the body and that adipose tissue

may regulate collagen and elastic fibre abundance in the dermis via the expression of

matrix metalloproteinase-9 (MMP9) (Fenske and Lober 1986; Sherratt 2015).



5.3



Skin Remodelling by Environmental Factors



There are two broadly accepted categories of skin ageing: intrinsic and extrinsic.

Intrinsic ageing refers to the naturally occurring degenerative process that causes fine

wrinkling and a gradual loss of elasticity and dermal matrix proteins with the passage of time (El-Domyati et al. 2002). These degenerative processes may be due to

systemic ageing mechanisms such as telomere shortening, cellular senescence and

oxidative stress and aberrant glycation which are thought to affect multiple organ

systems (Holliday 2006). In contrast, the second category of skin ageing, extrinsic

ageing, is characterised by the formation of coarse wrinkles, mottled pigmentation

and a marked loss of elasticity and resilience (El-Domyati et al. 2002; Yaar and

Gilchrest 2007). These outward manifestations are accompanied by profound and

localised remodelling of the dermal matrix [for a comprehensive review see (Naylor

et al. 2011)]. In the latter part of this section we discuss the potential role played by

smoking and environmental pollution in mediating extrinsic ageing, but first we

concentrate on the major causative factor: UVR. The term photo aged is often used

to describe chronically UV-exposed skin but this usage implies that UVR-exposure

promotes remodelling via the same processes which induce intrinsic ageing.

However, given the marked compositional, architectural and functional differences

between intrinsically aged and “photo aged” skin, it seems more appropriate to refer

to the process of photo damage rather than photo ageing.



5.3.1



Ultraviolet Radiation Exposure and Skin

Photo-Damage



The key molecular targets and potential mediators of UVR-induced dermal

remodelling are depicted in Fig. 5.1. In severely photoaged skin there is both a

widespread loss of fibrillar collagens (I and III) throughout the dermis and a



5 Skin Extracellular Matrix and Environmental Exposure



111



UV irradiaƟon



UV irradiaƟon



Epidermis

Dermalepidermal

juncƟon



Collagen

fibrils



Fibrillin-rich

microfibrils



ROS



ROS



UV-damaged

microfibrils

LTBP/LLC



Dermis



Cross-linking



TGFβ

receptors



TGFβ



ROS

Fibroblasts



Elastin



(1) Non-photodamaged



ROS

ROS



Proteases



(2) Mild photodamage



ROS



Elastosis?



(3) Severe photodamage



Fig. 5.1 Molecular mechanisms and consequences of chronic UVR-exposure. 1 Ordered fibrillin

—rich microfibrils, originating in the reticular dermis, form candelabra-like structures at the

dermal-epidermal junction. As well as providing a template for elastin deposition, fibrillin—rich

microfibrils regulate TGF b bioavailability within the ECM by binding the LTBP/LLC complex. 2

In early photodamage the fibrillin-rich microfibrils are diminished from the upper dermis. The

generation of ROS by cells in the epidermis in response to UV may activate dermal proteases to

target microfibrils and disrupt LTBP/LLC binding resulting in aberrant TGF-b/fibroblast

signalling. In addition, chromophoric amino acids within the primary sequence of the

LTBP/LLC may render the assembly susceptible to damage by UV. Further, the complex may

be displaced by proteolytic fibrillin fragments competing for binding sites along the length of

remaining intact microfibrils. 3 Crosslinking of collagen fibrils, driven by ROS, occurs in

extensive photodamage. The crosslinking of collagen may also drive ROS formation resulting in

increased protease activity and degradation of fibrillin-rich microfibrils. It has yet to be elucidated

if TGF b/fibroblast signalling results in the de novo deposition of elastin (elastosis) or the

aggregation of resident mature dermal elastic fibres in photodamage



localised loss of collagen VII anchoring fibrils at the DEJ (El-Domyati et al. 2002;

Talwar et al. 1995). In contrast, in the same tissue, dermal GAG content (in particular HA and chondroitin sulphate containing GAGs) is increased and

co-localised with the elastic fibre network (Bernstein et al. 1996). It has become

clear that this complex elastic fibre network is particularly sensitive to

UVR-exposure [for a comprehensive review see (Naylor et al. 2011)]. For example,

mildly photo-damaged skin is characterised by the loss of both the fibrillin

microfibril candelabra-like structures (oxytalan fibres) and fibulin-5 in the papillary

dermis whilst chronic UVR exposure induces profound dermis-wide changes in

elastic fibre architecture (Kadoya et al. 2005; Watson et al. 1999). In such severely

photo-damaged skin, the ordered arrangements of elastic and elaunin fibres in the

reticular dermis (which differ in their proportion of elastin and fibrillin) and of

fibrillin-microfibril containing oxytalan fibres in the papillary dermis is replaced by

a disordered mass of elastin and fibrillin-rich “elastotic” material. This remodelling

of the dermal ECM occurs in parallel with epidermal thickening and a flattening of



112



K.T. Mellody et al.



the rete ridges which normally characterise the DEJ in many sun-protected sites

(El-Domyati et al. 2002). However, the extent to which changes in dermal composition and architecture drive outward changes in skin appearance (specifically the

formation of deep wrinkles) remains unknown. Furthermore, the relative contributions of potential causative mechanisms of dermal remodelling remain (such as

UV-activation of the elastin promoter or by protease-mediated disruption of the

existing elastic fibres network) are still under investigation (Sellheyer 2003; Uitto

2008). The next section discusses the potential roles played by cellular and acellular

pathways in remodelling of the chronically sun-exposed dermis.



5.3.2



Mechanisms of Ultraviolet Radiation Induced Skin

Remodelling



It is now well established that UV-exposure induces the expression of multiple proteases including many ECM-degrading matrix metalloproteinases (MMPs), but it is

also evident that the substrate specificity of these enzymes is low [for a comprehensive

review see (Watson et al. 2014)]. MMPs-1 and -9 for example, whose expression is

upregulated in UVR exposed skin, can, collectively, degrade collagens I, III, IV and

VII, elastin and the ubiquitous adhesive glycoprotein fibronectin (Chakraborti et al.

2003; Fisher et al. 1996). As a consequence, if these enzymes were the main mediators

of photo damage then the early stages of UVR-exposure would be characterised by

disruption of the DEJ (collagen IV and VII), the dermal fibrillar collagen matrix

(collagens I and III), the elastic fibre system (elastin) and cell-matrix adhesion (fibronectin). However, as we have discussed in the previous section, it is components of

the elastic fibre system, and in particular fibrillin microfibril bundles which appear to

act as sensitive biomarkers of both mild and severe photo damage. We therefore

proposed in 2010 that the amino acid composition of fibrillin-microfibrils (which are

rich in UV-absorbing disulphide bonded Cys residues) would render them particularly

susceptible to damage from direct UVR exposure and in 2014, that photoageing/

photodamage may be due to both cellular and acellular pathways (the selective

multi-hit model) (Sherratt et al. 2010; Watson et al. 2014).

We were not the first group to recognise the potential for UVR to damage

extracellular dermal proteins either directly or via the production of reactive oxygen

species (ROS), a process known as photosensitization (Pattison et al. 2011).

Compelling evidence for the role of photosensitization in photoageing was provided

by Sander and colleagues who characterised the UVR-dose dependent accumulation of oxidation-induced protein carbonyls in the acutely exposed human papillary

dermis (Sander et al. 2002). Crucially however, the main protein targets of this

oxidative damage were not identified. It has been generally assumed that the major

structural proteins (fibrillar collagens and elastin) will be targets of UVR and ROS

and there are numerous in vitro studies which report the UV-mediated degradation

of collagen [i.e. (Jariashvili et al. 2012)]. In our 2014 review we related the UVR

doses used in these in vitro studies to the minimal erythemal dose (MED) which



5 Skin Extracellular Matrix and Environmental Exposure



113



will cause reddening of the skin (Watson et al. 2014). It was clear from this analysis

that fibrillar collagen are readily degraded by non-physiological UV wavelengths

(UVC) and doses (2–4 orders of magnitude greater than the MED). In contrast, we

have shown that physiologically relevant UV sources and doses (up to an MED of

UVA and UVB containing solar simulated radiation: SSR) have minimal effect on

the structure and/or electrophoretic mobility of proteins (collagens I and VI,

tropoelastin and a-lens crystallin) which are largely devoid of the UVA chromophoric amino acid residues (Cys, Trp and Tyr). In the same study, however, we

also demonstrated that: (i) UVA chromophore-rich proteins (fibrillin-1 microfibrils,

fibronectin b- and c-lens crystallins) are susceptible to the same low SSR doses and

that (ii) UV-exposed tissues are enriched in Cys, Tyr and Trp-containing proteins

(Hibbert et al. 2015). This latter observation lead us to propose that UVchromophore-rich proteins may act as endogenous sunscreens, protecting deeper

components from UV-exposure.



5.3.3



Infrared Radiation and Tobacco Smoke



Although it is the most intensively studied, UVR is not the only environmental

factor which is thought to promote skin ageing. In common with UVR, chronic

exposure to infrared radiation (IR: ranging in wavelength from 760 nm to 1 mm)

may also be associated with dermal elastosis and additionally with epidermal

remodelling [for a comprehensive overview the reader is referred to two excellent

reviews (Akhalaya et al. 2014; Schieke et al. 2003)]. The mechanisms which induce

these changes in IR exposed skin remain to be fully characterised but exposure to

IR can upregulate MMP-1 expression in cultured dermal fibroblasts, dysregulate

TGFb signalling and may promote oxidative stress (Akhalaya et al. 2014;

Grether-Beck et al. 2014; Karu 1999; Schieke et al. 2002). In addition to radiation

(UV and IR), the structure and function of human skin may be affected by the

exogenous chemicals found in tobacco smoke.

The phenomenon of the deeply wrinkled “smoker’s face” is often reported but

not universally accepted and may be influenced by the ethnicity of the subjects

(Daniell 1971; O’Hare et al. 1999). The histological consequences of smoking in

skin are also contentious. In UVR-exposed facial skin, smoking is associated with

enhanced solar elastosis (Boyd et al. 1999). In order to separate the effects of

UVR-exposure from the systemic effects of smoking, Allen and co-workers (in a

predominantly non-Caucasian population) and more recently Knuutinen and colleagues examined the histological distribution of elastic fibres in upper-inner arm

skin but were unable to identify any smoking-related differences (Allen et al. 1973;

Knuutinen et al. 2002). In contrast, immuno-histochemical studies have identified

non-elastosis-like deposition of elastin and increased elastic fibre deposition in the

upper inner arm and foreskin respectively of smokers (Frances et al. 1991; Just et al.

2005; Rosado et al. 2012). The apparent absence of fibrillar collagen remodelling in

the skin of smokers suggests that, in common with photo ageing/photo damage, the



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