An Essential Role for Resident Fibroblasts in Experimental Lung Fibrosis Is Defined by Lineage-Specific Deletion of High-Affinity Type II Transforming Growth Factor β Receptor

Rationale: Fibrotic response to lung injury depends on development of a fibrogenic population of myofibroblasts. The importance of resident interstitial fibroblasts and role of transforming growth factor beta (TGF beta) in this process is unclear. Objectives: To define the importance of TGF beta signaling in resident lung fibroblasts in the development of experimental pulmonary fibrosis. Methods: A compound genetic strategy in which mice homozygous for a floxed high-affinity type II TGF beta receptor (T beta RII) allele were crossed with a transgenic strain harboring a fibroblast-specific transgene encoding ligand-dependent Cre-recombinase was used. T beta RII was deleted by postnatal administration of tamoxifen over 5 days to compound mutant mice with appropriate littermate controls. II lumina microarray gene profiling and quantitative reverse transcriptase-polymerase chain reaction were used to confirm anergy to TGF beta in explanted lung fibroblasts. Bleomycin lung injury was used to induce lung fibrosis, which was analyzed by histology and biochemical methods. Immunofluorescence was used to define cell populations after lung injury. Measurements and Main Results: There was significant attenuation of fibrosis in mice after deletion of T beta RII in resident fibroblasts. At 7 days after injury the number of fibrocytes and myofibroblasts was substantially reduced. Potential regulators of fibrosis were suggested by gene expression profiles that identified key candidate profibrotic genes, including connective tissue growth factor and endothelin-1 expressed by wild-type but not mutant lung fibroblasts. Conclusions: Intact TGF beta signaling in resident pulmonary fibroblasts is essential for pulmonary fibrosis to develop. Our data support a key regulatory role of these cells in determining fibrocyte recruitment and myofibroblast differentiation.