Abstract
BackgroundCollagen-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.ResultsOur 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.ConclusionsInterventions 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.
Highlights
Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues
While this combination of markers has traditionally been considered sufficient for the identification of fibrocytes [8], accumulating data from our group and from others indicate that this combination of markers may identify a heterogeneous population of cells [6,7]
If the CD14+ collagen expressing cells seen in our model are fibrocytes, it is possible that their contributions to disease in this setting would include the fibrocyte functions typically attributed to macrophages such as cytokine and chemokine production [9], antigen presentation [31], inflammatory cell trafficking and activation [9] and promotion of angiogenesis [32], as well as the extracellular matrix (ECM)-producing and wound contractile properties typically attributed to activated myofibroblasts
Summary
Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues. The current paradigm of pulmonary fibrosis pathogenesis includes recurrent epithelial cell death responses with subsequent recruitment of a monocyte-derived inflammatory infiltrate and the eventual development of myofibroblast activation [13] These events are believed to be heavily influenced by TGF-b1 [14,15,16,17]. Elevations in circulating and/ or tissue CD45+Col-I+ cells have are seen in a broad array of fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF) [4], asthma [5], post-transplant bronchiolitis obliterans syndrome [21], and scleroderma [6]. Many of these diseases are associated with abnormalities in apoptosis [19,22,23]; a relationship between CD45+Col-I+ cells, fibrocytes, and apoptosis has not been previously assessed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
