Differences in the Fibrogenic Response after Transfer of Active Transforming Growth Factor-β1 Gene to Lungs of “Fibrosis-prone” and “Fibrosis-resistant” Mouse Strains

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Abstract
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-β1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-β1 despite higher levels of the transgene protein in the lung. This was not due to a general unresponsiveness of cells to TGF-β1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-β1 in vitro to the same degree. However, TGF-β1 induced a strong upregulation of tissue inhibitor of me...