Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. Methods: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wildtype mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. Measurements and Main Results: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased a-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. Conclusions: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.Keywords: alveolar epithelial cell; adhesion strength; epithelial-tomesenchymal transition; Smad2; CD9 Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology; the condition has a poor prognosis, and there are no effective treatments. IPF is characterized by progressive deposition of collagen and other extracellular matrix (ECM) molecules (1). Previously, IPF was viewed as a "smoldering" inflammatory response that ultimately led to chronic lung injury with subsequent fibrosis. However, inflammation is now not regarded as crucial to the etiology, largely because current antiinflammatory therapies for IPF have provided little benefit for patients (2). Instead, it has become clear that abnormal behavior of alveolar epithelial cells (AECs) is a primary source of the development of pulmonary fibrosis (3, 4). The disease process is initiated through repetitive injury of AECs, causing AEC activation, which in turn leads to recruitment of immune cells and fibroblasts within the lung microenvironment. Aberrant activated AECs, in cooperation with migrated immune cells and fibroblasts, secrete and activate latent transforming growth factor (TGF)-b 1 , as well as other profibrotic factors, which promote the differentiation of fibroblasts and AECs to myofibroblasts, resulting in overproduction of ECM in the lung.The tet...

CD151 represses mammary gland development by maintaining the niches of progenitor cells

“…41 Consistent with this notion was a marked increase in the active form of SMAD2, as well as expression of total SMAD4, upon CD151 removal (Fig. 6A).…”

“…This observation is consistent with a recent study on the in vivo effect of CD151 removal in another epithelial tissue. 41 Our unpublished data, however, do suggest that altered TGFb-mediated signaling in mammary tissues may not stem from a direct effect of CD151. Rather, it may result from CD151-mediated activation of Slug.…”

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

“…This model is supported by studies demonstrating that pulmonary fibrosis can occur following the ablation of factors that normally maintain epithelial integrity without any preceding inflammation (25,39,45). The model suggests that chronic injury results in the activation of a subset of bronchial and AEC that become hyperplastic with enlarged cell shape, whereas another subset of alveolar type II cells that are sensitive to chronic injuries undergo cell-flattening events.…”

“…A current model of IPF suggests that compromised epithelial integrity is a major component of pathogenesis and may in fact initiate the fibrotic response (16,20,29,34,39). This model is supported by studies demonstrating that pulmonary fibrosis can occur following the ablation of factors that normally maintain epithelial integrity without any preceding inflammation (25,39,45).…”

Genetic Ablation of the Tetraspanin CD151 Reduces Spontaneous Metastatic Spread of Prostate Cancer in the TRAMP Model

“…Molecular studies involving CD151 with cancer progression and metastasis to date have focused on in vitro and grafting models. These studies have shown that knockdown/-out or mutation of CD151 decreases cell motility (16)(17)(18)(19)(20)(21)(22) and/or decreases experimental metastasis (23)(24)(25)(26).…”