During wound healing as well as during fibrosis development, fibroblastic cells modulate into myofibroblasts and acquire the capacity of inducing connective tissue retraction and of synthesizing high amounts of extracellular matrix components, such as collagen type I (for review see Serini and Gabbiani, 1999). The most accepted marker of myofibroblastic modulation is the expression of -smooth muscle (sm) actin, the actin isoform typical of vascular smooth muscle cells. -Sm actin is expressed temporarily during granulation tissue evolution and more permanently in fibrotic situations. Several cytokines and/or growth factors influence myofibroblastic modulation but TGF-1 is the most important inducer of -sm actin synthesis. The action of TGF-1 is controlled by the concurrent expression of cellular fibronectin and in particular of the fibronectin isoform ED-A. Fibronectin ED-A is indispensable for the stimulation by TGF-1 of both -sm actin and collagen type I synthesis, whereas it does not interfere in the stimulation by TGF-1 of plasminogen activator inhibitor 1. Thus, the combined action of a growth factor and an extracellular matrix component are necessary in order to elicit myofibroblastic transformation. The question remains open as to what are the agents influencing the production of TGF-by inflammatory cells.
Using the experimental model of bleomicine-induced pulmonary fibrosis, our laboratory has recently shown that GM-CSF is capable of stimulating the production of TGF-1 by both macrophages and polymorphonuclear cells migrated in the alveolus early after bleomicine administration (Andreutti et al., 1998). Thus, it appears that GM-CSF may be the early initiator of a cascade reaction, which terminates with fibrosis formation, passing through TGF-production by inflammatory cells and a-sm actin and collagen production by fibroblastic cells.
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