Extensive research on skin aging in the last decade has resulted in an improved understanding of the pathophysiology of intrinsic (age-related) and extrinsic (UV-mediated photoaging) aging. Biochemical processes resulting in skin damage following exposure to UV radiation are now being identified and understood (1) . A correlation between biochemical processes following photodamage and creation of wound is emerging. Of specific interest to cosmeceutical manufacturers are the effects of growth factors in the process of wound healing. Table 4.1 shows the stages of wound healing and role of growth factors in each stage. Growth factors are regulatory proteins that mediate signaling pathways between and within cells. After a wound has been inflicted, a variety of growth factors flood the wound site and interact synergistically to initiate and coordinate each phase of wound healing. They help recruit and activate fibroblasts to induce rapid production of the extracellular matrix to close the wound followed by stimulation and multiplication of keratinocytes to form the new epidermis. The overall process is complex and not completely understood (2) .
Inflammation is induced as a result of formation of a wound or UV damage via several pathways including nuclear factorkappa B (NF- κ B)-mediated activation of tumor necrosis factor- α (TNF- α ) and interleukins (3) . Reactive oxygen species (ROS) and proteolytic enzymes are generated as a result of inflammation which causes degradation of the extracellular matrix. ROS increase oxidative phosphorylation of cell surface receptors causing activation of transcription factors activator protein 1 (AP-1) and NF- κ B, two critical components of the MAP kinase signaling pathway (4) . ROS therefore play a central role in intrinsic and extrinsic aging. AP-1 stimulates transcription of matrix metalloproteinase (MMP) growth factor genes in fibroblasts and keratinocytes, and inhibits type 1 procollagen gene expression in fibroblasts (5) . Multiple studies have shown that increased secretion of MMPs resulting from intrinsic and extrinsic aging results in breakdown of the dermal matrix (6) . MMP-1 (collagenase) produces cleavage at a single site in central triple helix of fibrillar type I and type III collagen. The cleaved subunits are further degraded by MMP-3 (stromelysine 1) and MMP-9 (gelatinase). Tissue inhibitors of metalloproteinase (TIMP) decrease activity of MMPs providing a mechanism to balance MMP activity. ROS inactivate TIMPs by oxidation and indirectly increase MMP activity.
AP-1-mediated reduction in the synthesis of procollagen appears to result from two mechanisms, interference of AP-1 with type 1 and type 3 procollagen gene transcription and blocking the profibrotic effects of TGF- β by impairment of TGF- β type 2 receptor/Smad pathway (3) . Activation of NF- κ B stimulates transcriptions of pro-inflammatory cytokine genes including IL-1, TNF- α , IL-6, and IL-8 (4) . Inflammation resulting from these cytokines increases secretion of ROS and more cytokines, further enhancing the effect of UV exposure. Inflammation causes protease-mediated degradation of elastin and UV exposure causes formation of abnormal elastin by fibroblasts. UV light is also an inhibitor of leucocyte elastase thereby increasing accumulation of elastotic materials (7) . The accumulation of elastotic materials is accompanied by degeneration of the surrounding collagenous network. The overall effects of these interlinked biochemical activities is the reduction of procollagen synthesis, increase of collagen degradation in the dermal extracellular matrix, and increase in irregular elastin deposition. Successful resolution of damage to skin and wound healing requires a balance between development of inflammation and its rapid resolution which includes involvement of growth factors and cytokines such as TGF- β , TNF- α , PDGF, IL-1, IL-6, and IL-10 (8) . Intrinsic aging does not show the inflammatory component seen with healing of acute photodamage and wounds, instead, mitochondrial oxidative metabolism produces some of the key mediators of extracellular matrix degradation including ROS (9) .
During wound healing, transition from inflammatory to granulation phase is mediated by a variety of growth factors and cytokines including PDGF, TGF- α , TGF- β , FGFs, IGF-1, CSF, ILs, and TNF- α (10) . These growth factors and cytokines are derived from macrophages, epidermal keratinocytes, and fibroblasts. Multiple metabolic pathways lead to the formation of new collagen and repair of extracellular matrix during the granulation phase. The final stage of wound healing after granulation and wound re-epithelialization or peeling of sunburned skin is the beginning of dermal tissue remodeling. During this stage, low strength, unorganized type 3 collagen and elastin structures produced during the ECM production phase are replaced by stronger type 1 collagen and structured elastin fibers to provide strength and resiliency to the dermis. This remodeling phase can last for several months and is the key to reversing the visible effects of skin aging (11) .
References :
1. Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 1989; 21: 610–13.
2. Mehta RC, Fitzpatrick RE. Endogenous growth factors as cosmeceuticals. Dermatol Ther 2007; 20: 350–9.
3. Quan T, He T, Kang S, et al. Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smadsignaling. Am J Pathol 2004; 165: 741–51.
4. Fisher GJ, Talwar HS, Lin J, et al. Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 1998; 101: 1432–40.
5. Schwartz E, Cruickshank FA, Christensen CC, et al. Collagen alterations in chronically sun-damaged human skin. Photochem Photobiol 1993; 58: 841–4.
6. Fisher GJ, Wang ZQ, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 1997; 337: 1419–28.
7. Martin P. Wound healing—aiming for perfect skin regeneration. Science 1997; 276: 75–81.
8. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127: 514–25.
9. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273: 59–63.
10. Moulin V. Growth factors in skin wound healing. Review article. Eur J Cell Biol 1995; 68: 1–7.
11. Fitzpatrick RE, Rostan EF. Reversal of photodamage with topical growth factors: a pilot study. J Cosmet Laser Ther 2003; 5: 25–34.
Inflammation is induced as a result of formation of a wound or UV damage via several pathways including nuclear factorkappa B (NF- κ B)-mediated activation of tumor necrosis factor- α (TNF- α ) and interleukins (3) . Reactive oxygen species (ROS) and proteolytic enzymes are generated as a result of inflammation which causes degradation of the extracellular matrix. ROS increase oxidative phosphorylation of cell surface receptors causing activation of transcription factors activator protein 1 (AP-1) and NF- κ B, two critical components of the MAP kinase signaling pathway (4) . ROS therefore play a central role in intrinsic and extrinsic aging. AP-1 stimulates transcription of matrix metalloproteinase (MMP) growth factor genes in fibroblasts and keratinocytes, and inhibits type 1 procollagen gene expression in fibroblasts (5) . Multiple studies have shown that increased secretion of MMPs resulting from intrinsic and extrinsic aging results in breakdown of the dermal matrix (6) . MMP-1 (collagenase) produces cleavage at a single site in central triple helix of fibrillar type I and type III collagen. The cleaved subunits are further degraded by MMP-3 (stromelysine 1) and MMP-9 (gelatinase). Tissue inhibitors of metalloproteinase (TIMP) decrease activity of MMPs providing a mechanism to balance MMP activity. ROS inactivate TIMPs by oxidation and indirectly increase MMP activity.
AP-1-mediated reduction in the synthesis of procollagen appears to result from two mechanisms, interference of AP-1 with type 1 and type 3 procollagen gene transcription and blocking the profibrotic effects of TGF- β by impairment of TGF- β type 2 receptor/Smad pathway (3) . Activation of NF- κ B stimulates transcriptions of pro-inflammatory cytokine genes including IL-1, TNF- α , IL-6, and IL-8 (4) . Inflammation resulting from these cytokines increases secretion of ROS and more cytokines, further enhancing the effect of UV exposure. Inflammation causes protease-mediated degradation of elastin and UV exposure causes formation of abnormal elastin by fibroblasts. UV light is also an inhibitor of leucocyte elastase thereby increasing accumulation of elastotic materials (7) . The accumulation of elastotic materials is accompanied by degeneration of the surrounding collagenous network. The overall effects of these interlinked biochemical activities is the reduction of procollagen synthesis, increase of collagen degradation in the dermal extracellular matrix, and increase in irregular elastin deposition. Successful resolution of damage to skin and wound healing requires a balance between development of inflammation and its rapid resolution which includes involvement of growth factors and cytokines such as TGF- β , TNF- α , PDGF, IL-1, IL-6, and IL-10 (8) . Intrinsic aging does not show the inflammatory component seen with healing of acute photodamage and wounds, instead, mitochondrial oxidative metabolism produces some of the key mediators of extracellular matrix degradation including ROS (9) .
During wound healing, transition from inflammatory to granulation phase is mediated by a variety of growth factors and cytokines including PDGF, TGF- α , TGF- β , FGFs, IGF-1, CSF, ILs, and TNF- α (10) . These growth factors and cytokines are derived from macrophages, epidermal keratinocytes, and fibroblasts. Multiple metabolic pathways lead to the formation of new collagen and repair of extracellular matrix during the granulation phase. The final stage of wound healing after granulation and wound re-epithelialization or peeling of sunburned skin is the beginning of dermal tissue remodeling. During this stage, low strength, unorganized type 3 collagen and elastin structures produced during the ECM production phase are replaced by stronger type 1 collagen and structured elastin fibers to provide strength and resiliency to the dermis. This remodeling phase can last for several months and is the key to reversing the visible effects of skin aging (11) .
References :
1. Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 1989; 21: 610–13.
2. Mehta RC, Fitzpatrick RE. Endogenous growth factors as cosmeceuticals. Dermatol Ther 2007; 20: 350–9.
3. Quan T, He T, Kang S, et al. Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smadsignaling. Am J Pathol 2004; 165: 741–51.
4. Fisher GJ, Talwar HS, Lin J, et al. Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 1998; 101: 1432–40.
5. Schwartz E, Cruickshank FA, Christensen CC, et al. Collagen alterations in chronically sun-damaged human skin. Photochem Photobiol 1993; 58: 841–4.
6. Fisher GJ, Wang ZQ, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 1997; 337: 1419–28.
7. Martin P. Wound healing—aiming for perfect skin regeneration. Science 1997; 276: 75–81.
8. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127: 514–25.
9. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273: 59–63.
10. Moulin V. Growth factors in skin wound healing. Review article. Eur J Cell Biol 1995; 68: 1–7.
11. Fitzpatrick RE, Rostan EF. Reversal of photodamage with topical growth factors: a pilot study. J Cosmet Laser Ther 2003; 5: 25–34.