Mechanical Stretch Induces Epithelial-Mesenchymal Transition in Alveolar Epithelia via Hyaluronan Activation of Innate Immunity

Abstract

Epithelial injury is a central event in the pathogenesis of many inflammatory and fibrotic lung diseases like acute respiratory distress syndrome, pulmonary fibrosis, and iatrogenic lung injury. Mechanical stress is an often underappreciated contributor to lung epithelial injury. Following injury, differentiated epithelia can assume a myofibroblast phenotype in a process termed epithelial to mesenchymal transition (EMT), which contributes to aberrant wound healing and fibrosis. We demonstrate that cyclic mechanical stretch induces EMT in alveolar type II epithelial cells, associated with increased expression of low molecular mass hyaluronan (sHA). We show that sHA is sufficient for induction of EMT in statically cultured alveolar type II epithelial cells and necessary for EMT during cell stretch. Furthermore, stretch-induced EMT requires the innate immune adaptor molecule MyD88. We examined the Wnt/␤-catenin pathway, which is known to mediate EMT. The Wnt target gene Wnt-inducible signaling protein 1 (wisp-1) is significantly up-regulated in stretched cells in hyaluronan-and MyD88-dependent fashion, and blockade of WISP-1 prevents EMT in stretched cells. In conclusion, we show for the first time that innate immunity transduces mechanical stress responses through the matrix component hyaluronan, and activation of the Wnt/␤-catenin pathway.Epithelial injury is now recognized as a primary event in the pathogenesis of lung disease (1). Alveolar cells consist of type I epithelia (AT1), 2 which serve gas exchange, and type II epithelia (AT2), which produce surfactant and are now recognized as the critical responders to lung injury. Although AT1 cells usually undergo cell death after critical injury, AT2 cells can present a variety of responses, including proinflammatory response, proliferation, differentiation to AT1 epithelia, or epithelial-tomesenchymal transition (EMT). The AT2 response to injury may ultimately lead to restoration of pulmonary architecture and function, or to dysregulated repair, fibrosis, and respiratory failure (2). The factors that promote regulated or pathological repair are incompletely understood. However, it is often forgotten that alveolar epithelia are not static cells. Alveolar epithelia undergo continuous cyclic stretch during ventilation; moreover, pathologically high levels of stretch are exerted on alveolar epithelia either as a consequence of injury (anatomical distortion from scarring) or iatrogenically (mechanical ventilation). The response of alveolar epithelia to injury must therefore be seen in the context of mechanical strain. The importance of stretch injury as a cause of lung disease is exemplified in the acute lung injury of critically ill patients, which is estimated at 200,000 cases in the United States annually (3). Mechanical ventilation is crucial for survival of these patients; however, it often leads to ventilator-induced lung injury (VILI) with pulmonary edema, inflammation, and fibrosis, leading to respiratory failure and death.Epithelial injury is central to the pa...

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

“…3 Recent studies using alveolar type II epithelial cells and rats have demonstrated that cyclic mechanical stretch can lead to disorganization and ECM remodeling of the lung by activating the Wnt/b-catenin pathway and inducing EMT. 6,7 In the current mouse model of VILI, we demonstrated that mechanical ventilation of bleomycintreated lungs of mice increased lung fibrogenesis, lung edema, microvascular permeability, fibroblast accumulation, epithelial apoptosis, hypoxemia, and PAI-1 and TGF-b1 production. Upregulation of Src is associated with increased lung injury.…”

Mechanical Ventilation Augments Poly(I:C)-Induced Lung Injury via a WISP1-Integrin β3-Dependent Pathway in Mice

“…Konigshoff et al (10) also demonstrated that WISP1 is a potential therapeutic target for pulmonary fibrosis. Heise and colleagues (11) reported that WISP1 was induced by mechanical stretch in mouse alveolar type II cells, and the increased WISP1 expression level could be reduced in cells treated with a WISP1 antibody. These studies indicate that WISP1 contributes to the process of lung injury.…”

Research on WISP1 in Lung Disease

“…Alveolar-capillary permeability, which can be used to determine the extent of lung injury, is actually proportional to WISP1secreted in vivo after high tidal volume ventilation. Heise [48] found that WISP1 is significantly up-regulated in stretched type II epithelia in a hyaluronanand MyD88-dependent fashion; meanwhile, the epithelial mesenchymal transition in stretched cells can be prevented by using WISP1 antibody. Faisyet al [49] have also identified that stretch led to significantly higher mRNA levels of WISP1.…”