title: Local apoptosis promotes collagen production by monocyte-derived cells in transforming growth factor β1-induced lung fibrosis.
abstract: BACKGROUND
  Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues. However, the precise identity of these cells and whether injury is required for their recruitment remain unknown. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human transforming growth factor (TGF)-β1 gene is targeted to the lung, we characterized the cell surface phenotype of collagen-containing CD45+ cells in the lung and tested the hypothesis that apoptotic cell death responses are essential to the accumulation of CD45+Col-I+ cells.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Mathai
authors.affiliation: Medimmune Ltd, Granta Park, Cambridge, CB21 6GH, UK.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Murray
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Russell
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Reilkoff
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Medicine, Central South University, Changsha, Hunan China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Gan
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, TAC 441S, New Haven, CT, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog