In the bleomycin model, inhibition of lymphocyte-, macrophage-, or fibroblast-mediated inflammatory mechanisms attenuates fibrosis. Thus it is reasonable to postulate that chronic inflammatory processes, as in the bleomycin-induced lesion, involve a macrophage-lymphocyte-fibroblast cellular axis, responsible for initiation and maintenance of chronic inflammation and fibrosis. Supporting this contention, the data discussed in this review may be synthesized into a model which integrates the participation of both soluble and cellular components of the profibrotic inflammatory lesion (Table 1). Immediately following intratracheal bleomycin challenge, proinflammatory mediators such as IL-1, IL-6, and TNF are present initially in the airway and alveoli of the rodent, which induces subsequent increases in MCP-1 and MIP-1α expression by alveolar macrophages and airway epithelial cells. Concomitantly, arachidonic acid metabolites and reactive oxygen species are being generated from resident macrophages and newly recruited neutrophils, contributing to the bleomycin-associated airway epithelial cell injury. As the lesion progresses, the chemoattractants MCP-1 and MIP-1α facilitate recruitment and activation of specific subsets of lymphocytes, eosinophils, and MΦ to the alveolar space. These cells in turn secrete cytokines, such as TGFβ, capable of causing the upregulation of procollagen expression and proliferation of myofibroblasts. Expression of growth factors and other profibrotic substances from the interstitial inflammatory nidus are the likely stimuli for collagen expression and deposition 1 to 2 wk post-bleomycin challenge. The macrophages, lymphocytes, and myofibroblasts present in the mature, bleomycin-induced, profibrotic inflammatory lesion may stimulate one another reciprocally, initiating and maintaining collagen synthesis via a complex network of chemokines and other soluble proinflammatory substances. Chemokine expression is an important characteristic of lung injury and fibrosis. It represents a starting point for investigation of the mechanisms responsible for unremitting fibrosis in the lungs of patients with fibrotic lung diseases as well as a potential target for therapeutic intervention. In this context, future experiments will investigate the expression of chemokine receptors and their regulation. In addition, work is ongoing to evaluate the cytokine profile of the predominant lymphocyte populations found in the fibrotic lesion (such as TH1 versus TH2). Finally, future experiments will examine the specific roles of MCP-1, MIP-1α, and additional chemokines in the initiation and maintenance of the profibrotic inflammatory lesion.
