Interleukin-1β Causes Acute Lung Injury via αvβ5 and αvβ6 Integrin–Dependent Mechanisms

Abstract

Abstract-Interleukin (IL)-1␤ has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1␤-mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1␤ production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the ␣v␤6 integrin and/or transforming growth factor-␤ attenuated the IL-1␤-induced ALI. The results of in vitro studies indicated that IL-1␤ caused the activation of transforming growth factor-␤ via RhoA/␣v␤6 integrin-dependent mechanisms and the inhibition of the ␣v␤6 integrin and/or transforming growth factor-␤ signaling completely blocked the IL-1␤-mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1␤ increased protein permeability across lung endothelial cell monolayers via RhoA-and ␣v␤5 integrin-dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the ␣v␤5 and ␣v␤6 integrins had an additive protective effect against IL-1␤-induced ALI. In summary, these results demonstrate a critical role for the ␣v␤5/␤6 integrins in mediating the IL-1␤-induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI. Key Words: lung Ⅲ cytokines Ⅲ inflammation Ⅲ endothelial cells Ⅲ epithelial cells Ⅲ rodents A cute lung injury (ALI) is a devastating clinical syndrome in critically ill patients with an overall mortality rate of 30% to 40%. 1 The syndrome is characterized by alveolar epithelial and lung endothelial injury leading to increased permeability across the alveolar-capillary barrier, pulmonary edema, and acute respiratory failure. 2 Despite an improved understanding of the pathogenesis of ALI in recent years, the molecular steps regulating the development of increased lung endothelial and epithelial permeability remain poorly understood, and no specific pharmacological therapies are currently available.During the early phase of ALI, a variety of inflammatory mediators are released into the distal air spaces. 2 Among those, interleukin (IL)-1␤ has been shown to be among the most biologically active cytokines in the lungs early after the onset of ALI. 3-5 Furthermore, IL-1␤ stimulates the production of a variety of chemokines (eg, IL-8, monocyte chemotactic protein [MCP]-1, and macrophage inflammatory protein [MIP]-1␣) 6 involved in epithelial wound repair 7,8 and is a potent inducer of lung fibrosis. 9,10 It has been previously shown in rats that lung vascular permeability increases after short-term exposure of IL-1␣ and IL-1␤ protein when ...

Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

“…84 Several excellent recent reviews have addressed integrin-mediated activation of TGF-␤ in the lung. 85,86 In mouse models of lung injury using ␤6 integrin subunit-null mice, ␣v␤6 integrin-mediated TGF-␤ activation has been implicated in lung permeability changes (high tidal volume, 68 bleomycin, LPS, 87 and interleukin [IL]-1␤-induced 88 ), surfactant homeostasis, 80 and fibrosis (bleomycin-and radiation-induced 27 ). Mechanisms involving alveolar/endothelial cell junction formation in lung permeability or epithelial mesenchymal transition in fibrosis have been proposed (Figure 2).…”

“…Mechanisms involving alveolar/endothelial cell junction formation in lung permeability or epithelial mesenchymal transition in fibrosis have been proposed (Figure 2). 88,89 Less is know of the role of the integrin ␣v␤6 in the airway. In vitro, integrin ␣v␤6-mediated TGF-␤ activation may play a role in promoting squamous metaplasia of airway epithelial cells.…”

“…Complete loss of ␤6 in knockout mice results in increased expression of MMP-12 by alveolar macrophages, which causes age-dependent airspace enlargement 81 and also increases susceptibility to pulmonary edema by increasing alveolar and endothelial permeability. 88 Increased expression of ␣v␤6 is associated with pulmonary inflammation and fibrotic lung disorders, and deficiency of ␤6 or antibody neutralization of ␣v␤6 in bleomycin or radiation-treated mice can decrease pulmonary fibrosis, 27,50,83 an effect that may in part be due to a role for ␣v␤6-mediated TGF-␤ activation in epithelial mesenchymal transition (EMT). 89 1366 Nishimura AJP October 2009, Vol.…”

Neuregulin-1-Human Epidermal Receptor-2 Signaling Is a Central Regulator of Pulmonary Epithelial Permeability and Acute Lung Injury

“…The cytokine interleukin-1␤ (IL-1␤) has been identified as a central mediator of epithelial permeability, ALI, and pulmonary fibrosis (23)(24)(25)(26)(27)(28)(29). Given that IL-1␤ and HER2 activation have both been implicated in the pathogenesis of lung injury, an interaction between the two signaling pathways is possible.…”

Targeted Delivery of Surface Modified Nanoparticles: Modulation of Inflammation for Acute Lung Injury

“…Recently, Ganter et al demonstrated a complete inhibition of pulmonary edema using anti-αvβ6 integrin and anti-TGF-antibodies in IL-1 instilled ALI model. 21 …”