Gene Expression Profiling of Pulmonary Fibrosis Identifies Twist1 as an Antiapoptotic Molecular “Rectifier” of Growth Factor Signaling

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into IPF pathogenesis, we performed gene expression profiling of IPF lungs. Twist1, a basic helix-loop-helix protein, was found among the most consistently and highly up-regulated genes and was expressed in nuclei of type II epithelial cells, macrophages, and fibroblasts in IPF lungs. We studied the function of Twist1 in fibroblasts further, because they are the major effector cells in this disease and persist despite an ambient proapoptotic environment. Twist1 was induced by the profibrotic growth factors (GFs) basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor in primary rat lung fibroblasts (RLFs). Suppression of Twist1 expression resulted in decreased RLF accumulation due to increased apoptosis, whereas Twist1 overexpression protected RLFs against several apoptotic stimuli. Addition of platelet-derived growth factor in combination with other GFs led to an increase in proliferation. When Twist1 was depleted, GFs continued to act as mitogens but caused a marked increase in cell death. The increase in apoptosis under basal or growth factorstimulated conditions was partly mediated by up-regulation of the proapoptotic Bcl-2 family members, Bim and PUMA. These findings indicate that Twist1 promotes survival and accumulation of fibroblasts by shaping their responsiveness to growth factor stimulation. We propose that Twist1 represents one of the factors that promotes pathogenic accumulation of fibroblasts in fibrotic lung disease. (Am J Pathol

Twist1 Is a Key Regulator of Cancer-Associated Fibroblasts

“…As Yang and colleagues first reported that Twist1 is a critical player in cancer metastasis (16), most studies focused on Twist1's role in cancer cells (22)(23)(24), with little attention paid to its possible role in the tumor microenvironment, including CAFs. In contrast to rare expression of Twist1 in adult normal fibroblasts, Twist1 is frequently and strongly expressed in embryonic fibroblasts (9,11,25) and pathologic fibroblasts in idiopathic pulmonary fibrosis (26,27) and desmoid tumor (28). Bridges and colleagues (26) reported that Twist1 enhanced survival and accumulation of fibroblasts in fibrotic lung disease, which is consistent with results of our current study.…”

“…In contrast to rare expression of Twist1 in adult normal fibroblasts, Twist1 is frequently and strongly expressed in embryonic fibroblasts (9,11,25) and pathologic fibroblasts in idiopathic pulmonary fibrosis (26,27) and desmoid tumor (28). Bridges and colleagues (26) reported that Twist1 enhanced survival and accumulation of fibroblasts in fibrotic lung disease, which is consistent with results of our current study. Bacac and colleagues (28) reported that Twist1 is highly expressed in desmoid tumors (neoplastic myofibroblastic lesions) compared with nodular fasciitis (nontumorous proliferation of fibroblasts).…”

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

“…end products, as potential regulators of lung fibrosis (6)(7)(8)(9)(10)(11)(12). Additionally, we and others have identified gene expression patterns that distinguish IPF from hypersensitivity pneumonitis, variants of disease that characterize distinct patterns of progression and characterize patients with pulmonary hypertension (9,(13)(14)(15)(16).…”

Chronic inflammation and lung fibrosis: pleotropic syndromes but limited distinct phenotypes

“…The demonstration of an increase in Twist1, a transcription factor that plays the role of master regulator of these processes, is consistent with the suggestive role of EMT in IPF. 23,24 The contribution of EMT to IPF, however, is an active topic of debate. 25,26 Regardless, the contribution of TGF-in fibrotic lung disease is not in question -it is both a target and an inducer of Twist1 and Twist1 is regulated through a feed-forward mechanism contributed both by Twist1 itself and nuclear factor-B, induced by inflammatory signals.…”