Progressive systemic sclerosis (PSS), is a connective tissue disease characterized by excessive accumulation of collagen in the skin and various internal organs which is due, at least in part, to increased collagen production by PSS fibroblasts. In order to examine the molecular mechanisms responsible for this abnormality, we compared the kinetics of collagen biosynthesis, the intracellular degradation of collagen and the expression of Types I and III procollagen genes between normal and PSS dermal fibroblasts in culture. Two age- and sex-matched normal and PSS dermal fibroblast cell lines were studied. The results showed that the PSS cultures produced higher amounts of collagen than did normal fibroblasts and displayed an abnormal kinetic pattern. Furthermore, the PSS cells showed a slight but statistically significant increase in the fraction of collagen degraded intracellularly when compared with normal cells (23% against 18% respectively). The levels of mRNA for procollagen Types I and III were determined by Northern and dot-blot hybridization with specific cloned cDNA probes for alpha 1(I), alpha 2(I) and alpha 1(III) and it was found that they were 2-3-fold higher for each of the three chains in the PSS cell lines compared with the controls. These findings indicate, therefore, that the overproduction of collagen characteristic of PSS fibroblasts can be largely accounted for by the increased levels of collagen mRNA.

A high suspicion for malignancy in chronic perineal fistulas associated with Crohn's disease should be maintained in spite of negative biopsies. Especially in women, the shorter duration of Crohn's fistulas prior to malignant degeneration necessitates an aggressive approach to rule out cancer.

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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.

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