Local apoptosis promotes collagen production by monocyte-derived cells in transforming growth factor β1-induced lung fibrosis

Our studies demonstrate that CD45+Col-I+ cells appearing in the TGF-β1-exposed murine lung express markers of the monocyte lineage. Inhibition of apoptosis via pharmacological caspase blockade led to a significant reduction in CD45+Col-I+ cells, which appear to accumulate independently of alternatively activated macrophages. There are also increased levels of apoptosis and greater numbers of CD45+Col-I+ in the lung tissue of patients with two distinct forms of fibrotic lung disease, idiopathic pulmonary fibrosis and connective tissue disease-related interstitial lung disease, when compared to lung from healthy normal controls. These findings are accompanied by an increase in collagen production in cultured monocytes obtained from subjects with fibrotic lung disease. Treatment of these cultured cells with the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD/fmk) reduces both apoptosis and collagen production in all subjects.Interventions that prevent collagen production by monocytes via modulation of caspase activation and of apoptosis may be ameliorative in monocyte-associated, TGF-β1-driven processes such as pulmonary fibrosis.The CD14+ fraction of peripheral blood contains heterogeneous monocyte progenitors with important roles in tissue injury and repair [1]. A subpopulation of monocytes differentiates into fibrocytes by acquiring a fibroblast-like morphology, gaining expression of collagen I and CD34 while losing CD14 expression [2]. Fibrocytes accumulate in transforming growth factor (TGF)-β1-exposed tissues [3] and are associated with an array of fibrosing disorders including asthma, pulmonary fibrosis, and scleroderma [4-6]. Due to the considerable variability in methods used to identify these cells, controversy exists as to their true phenotype [7,8] though the presence of fibrocytes in several forms of fibrosis is now well established. The mechanism(s) through which fibrocytes and related CD45+ collagen (Col)-I+ cell