Control of Collagen Deposition in Mammalian Lung

Abstract

This review considers the mechanisms controlling collagen deposition in mammalian lung in five different states: normal development, fibrosis, erosion, pneumonectomy, and the steady state. Deposition is the net result of positive and negative processes. The major positive processes are control of cell number and type, regulation of transcription and translation, post-translational modifications, fibril formation, and covalent cross-linking. The negative mechanisms are intracellular degradation, collagenase-mediated degradation, and phagocytosis, and they are integral to the life cycle of collagen. Cytokines and growth factors have many and complex effects on all the processes that constitute collagen metabolism. Interleukin-1 and tumor necrosis factor-alpha can either stimulate or inhibit collagen accumulation, presumably depending on the immediate environment. Interleukin-6 inhibits collagen degradation, and gamma-interferon inhibits collagen production. Platelet derived growth factor and fibroblast growth factor have powerful mitogenic effects on connective tissue cells in lung, and can also affect collagen production directly. Transforming growth factor-beta activates a battery of processes that uniformly contribute to accumulation of collagen. Transforming growth factor-beta may be the "master switch" for a fibrotic program in lung. Therapeutic approaches to controlling lung fibrosis by manipulating cytokine levels are promising. Prostaglandin E has uniformly negative effects on net collagen accumulation and may play a central role in an erosion program.

Interstitial fibrosis and growth factors.

“…Two recent findings may provide exciting future avenues for regulation of TGF-11 activity and therefore, lung fibrosis. Thrombospondin was found to be a major activator of TGF-,B1 by binding to and inducing a conformational change in the latency-associated peptide of TGF-P (148); and the integrin av16, which is upregulated on epithelial cells in response to lung inflammation, induces spatial activation ofTGF-,B1 (149 TGF-PI has numerous biologic activities including immunomodulatory (158), both pro-and antimitogenic (159,160), and profibrotic through increases in extracellular matrix synthesis and inhibition of matrix degradation (161). TGF-W_ inhibits proliferation of epithelial cells and thus could potentially extend the fibroproliferative phase following lung injury, since reepithelialization is purported to limit the formation of granulation tissue (162).…”

“…TGF-31 has been shown to influence collagen accumulation at many of the key stages in collagen metabolism and degradation, beginning with induction of procollagen gene transcription (161,165). A transgenic mouse containing a rat type 1 alpha-1 collagen promoter fused to the chloramphenicol acetyltransferase (CAT) reporter gene has been studied in dermal wound and bleomycin lung injury models, and revealed that subcutaneous injection of TGF-W1 increases the CAT transgene expression but only in a subpopulation of dermal fibroblasts, even though alpha-1 collagen was expressed throughout the dermis (166 Collagen synthesis and degradation is an ongoing process in the lung, and TGF-,B1 has been shown to reduce the proportion of procollagen that is degraded within lung fibroblasts prior to secretion (167).…”

“…A transgenic mouse containing a rat type 1 alpha-1 collagen promoter fused to the chloramphenicol acetyltransferase (CAT) reporter gene has been studied in dermal wound and bleomycin lung injury models, and revealed that subcutaneous injection of TGF-W1 increases the CAT transgene expression but only in a subpopulation of dermal fibroblasts, even though alpha-1 collagen was expressed throughout the dermis (166 Collagen synthesis and degradation is an ongoing process in the lung, and TGF-,B1 has been shown to reduce the proportion of procollagen that is degraded within lung fibroblasts prior to secretion (167). Furthermore, TGF-,1 is capable of limiting mature extracellular collagen degradation through altering the balance between collagenases and their inhibitors (161). TGF-,1I may even induce a negative feedback pathway that limits its own enhancement of procollagen production by inducing prostaglandin E2 (161).…”

“…Furthermore, TGF-,1 is capable of limiting mature extracellular collagen degradation through altering the balance between collagenases and their inhibitors (161). TGF-,1I may even induce a negative feedback pathway that limits its own enhancement of procollagen production by inducing prostaglandin E2 (161). Although TGF-3l is generally viewed as a profibrotic cytokine, investigators have entertained the hypothesis that TGF-, may be important in downregulating the T-helper (Th) 1 lymphocyte response in certain fibrotic lung diseases such as sarcoidosis, through inhibition of the production of cytokines (IL-2 and interferon gamma, for example) involved in propagation of granulomatous inflammation (168 Immunohistochemical staining for TGF-P1 in subjects with silicosis demonstrated dense staining within central hyalinized areas of the silicotic nodules and in scar tissue from areas with progressive massive fibrosis, whereas the TGF-,1 staining for subjects with acute silicosis was localized within macrophages and hyperplastic alveolar epithelium (171).…”

Lung inflammatory responses

“…Once monocytes reach the area of inflammation, they become activated and begin phagocytizing bacteria and damaged cells, including neutrophils and fibrin deposits and tissues. Collagenases and elastases are released from the macrophages that destroy connective tissue [22]. A plasminogen activator is released, resulting in the production of plasmin and the tissue matrix relaxes [73].…”