Abstract
While wound healing is completed, the epithelium functions to normalize the interstitial context by eliminating fibroblasts excited during matrix reconstruction. If not, tissues undergo pathologic fibrosis. Pulmonary fibrosis is a fatal and hardly curable disorder. We here tried to identify epithelium-derived cytokines capable of ameliorating pulmonary fibrosis. Human lung fibroblasts were inactivated in epithelial cell-conditioned media. Cystatin C (CST3) and growth differentiation factor 15 (GDF15) were found to be enriched in the conditioned media and to inhibit the growth and activation of lung fibroblasts by inactivating the TGF–Smad pathway. In mouse and human lungs with interstitial fibrosis, CST3 and GDF15 expressions were markedly reduced, and the restoration of these cytokines alleviated the fibrotic changes in mouse lungs. These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis.
Highlights
Pulmonary fibrosis is a chronic progressive lung disorder associated with excessive extracellular matrix (ECM) deposition and collapse of the lung parenchymal architecture, leading to severe respiratory dysfunction with a median survival of 2–4 years[1]
Given that BrdU-positive cell in the S phase were regarded as proliferative (Figure S1a), cell proliferation was halted in human pulmonary alveolar epithelial cells (hPAE) conditioned medium (CM) (Fig. 1b)
We evaluates the types of cell death by co-staining cells with annexin V and propidium iodide (Figure S1b), and found that hPAE CM provoked either apoptosis or necrosis in CCD-18Lu cells (Fig. 1d,e)
Summary
Pulmonary fibrosis is a chronic progressive lung disorder associated with excessive extracellular matrix (ECM) deposition and collapse of the lung parenchymal architecture, leading to severe respiratory dysfunction with a median survival of 2–4 years[1]. Anti-inflammatory and immunosuppressive drugs have been tested as therapeutic regimens for pulmonary fibrosis, but none have been sufficiently effective in prolonging the survival period of patients[2]. Nintedanib and pirfenidone were clinically tried and evaluated to delay the progression of fibrosis[4,5]. These drugs were reported to provoke serious adverse effects in the clinical trial[6,7,8].
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