Epithelial cell‐derived transforming growth factor‐β In bleomycin‐induced pulmonary injury

Abstract

We have investigated whether enhanced secretion of transforming growth factor-beta (TGF-beta) by distal respiratory epithelial cells was associated with the development of bleomycin-induced pulmonary fibrosis. Type 2 pneumocyte-enriched preparations of bronchioloalveolar epithelial cells from normal mouse lung tissue released latent TGF-beta when cultured in serum-free medium. TGF-beta in culture supernatants could be detected using a sensitive enzyme immunoassay which employed enzyme complex amplification as a reporter system, as well as by a radiolabelled receptor competition assay. Exposure to bleomycin and other potentially fibrogenic stimuli in vitro did not stimulate production of TGF-beta by the epithelial cells but release was enhanced by treatment of the cells with interferon-gamma. Type 2 pneumocyte-enriched cell preparations obtained following induction of a pulmonary inflammatory response by administration of intratracheal bleomycin to susceptible C57BL/6 mice did not demonstrate increased release of TGF-beta in culture. However, the concentration of TGF-beta in bronchoalveolar lavage (BAL) fluids was significantly elevated compared to controls at 1 and 2 weeks after bleomycin-induced injury in these mice. No such increase was detected in BAL fluids from BALB/c mice, which are resistant to the effects of bleomycin. These results provide no support for a pathogenetic role of alveolar epithelial cell-derived TGF-beta in bleomycin-induced pulmonary fibrosis. Nevertheless, elevated levels of TGF-beta in BAL fluids may provide a marker of the progression of pulmonary injury to fibrosis.

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

“…Another potential cellular target is macrophages. The critical profibrotic mediator TGF-β can derive from a variety of cell types, including fibroblasts themselves (63)(64)(65)(66). Our data with fibroblast-specific FOXM1-knockout mice implicate a role for the fibroblast in the generation of this mediator, along with the TGF-β target gene product CTGF.…”

The Role of Transforming Growth Factor β in Lung Development and Disease

“…This is consistent with findings in animals with bleomycininduced lung fibrosis. [62][63][64][65][66][67][68][69][70][71] In several studies, TGF␤ has been shown to be a marker of the activity of tissue repair and remodeling. In patients with sarcoidosis, Salez et al 48 found the levels of TGF␤1 to be increased only in patients with an active form of the disease associated with alterations in lung function and leading to fibrosis.…”

Serum-Free Culture of Mouse Tracheal Epithelial Cells

“…Production of TGF-P1 by AEC in culture was measured using a sandwich enzyme immunoassay sensitive to =50 pg/mL [13]. This utilized a mouse monoclonal antibody to TGF-P1,2 and 3 (Genzyme, Cambridge, MA, USA) for capture, a turkey polyclonal antibody to TGF-P1 (Collaborative Research, Waltham, MA, USA) for detection, and enzyme complex amplification [14] as a reporter system.…”