Integrin ␣ v ␤ 5 Regulates Lung Vascular Permeability and Pulmonary Endothelial Barrier Function

Lung Biology Center, Division of Pulmonary and Critical Care Medicine, Laboratory of Surgical Research, Department of Anesthesia, and Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 04/2007; 36(3):377-86. DOI: 10.1165/rcmb.2006-0238OC
Source: PubMed


Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alphavbeta5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta [TGF-beta]). Knockout mice homozygous for a null mutation of the integrin beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.

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Available from: Dean Sheppard, May 22, 2015
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    • "In addition, microscopy analysis explored that hypoxia alone induces slight alveolar epithelium and capillary endothelium disruption and swelling, while combined hypoxia and exercise significantly increased endothelium swelling and disruption. In the study, the alveolar-capillary permeability is measured to the integrity of alveolar-capillary barrier by Evan’s blue method [24,27]. Moreover, in our study, HR mice, present the medium situation symptoms that from normal to HAPE development, which could correspond to subclinical HAPE in human. "
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    ABSTRACT: High altitude pulmonary edema (HAPE) affects individuals and is characterized by alveolar flooding with protein-rich edema as a consequence of blood-gas barrier disruption. In this study, we hypothesized that aquaporin 5 (AQP5) which is one kind of water channels may play a role in preservation of alveolar epithelial barrier integrity in high altitude pulmonary edema (HAPE). Therefore, we established a model in Wildtype mice and AQP5 -/- mice were assingned to normoxic rest (NR), hypoxic rest (HR) and hypoxic exercise (HE) group. Mice were produced by training to walk at treadmill for exercising and chamber pressure was reduced to simulate climbing an altitude of 5000 m for 48 hours. Studies using BAL in HAPE mice to demonstrated that edema is caused leakage of albumin proteins and red cells across the alveolarcapillary barrier in the absence of any evidence of inflammation. In this study, the Lung wet/dry weight ratio and broncholalveolar lavage protein concentrations were slightly increased in HE AQP5 -/- mice compared to wildtype mice. And histologic evidence of hemorrhagic pulmonary edema was distinctly shown in HE group. The lung Evan's blue permeability of HE group was showed slightly increased compare to the wildtype groups, and HR group was showed a medium situation from normal to HAPE development compared with NR and HE group. Deletion of AQP5 slightly increased lung edema and lung injury compared to wildtype mice during HAPE development, which suggested that the AQP5 plays an important role in HAPE formation induced by high altitude simulation.Virtual slides: The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 11/2013; 8(1):193. DOI:10.1186/1746-1596-8-193 · 2.60 Impact Factor
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    • "Focal adhesions, sites of close contact between cell-cell and cell-extracellular matrix, are essential for normal cell growth, differentiation, inter-and intracellular communication, and tissue integrity (Mehta and Malik, 2006; Mehta et al., 2002). Among the protein complexes associated with focal adhesions, focal adhesion kinase (FAK) and paxillin play an important role in the transmission of integrininduced cytoplasmic signals and in the reorganization of actin cytoskeleton (Katsumi et al., 2004; Parsons, 2003; Su et al., 2007). FAK, an ~125-kDa tyrosine kinase, is activated primarily through integrin-mediated cell adhesion to extracellular matrix and to a lesser extent by growth factors, bioactive lipids, neuropeptides, and ROS (Mehta and Malik, 2006). "
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    ABSTRACT: Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating evidence indicates that 4-hydroxynonenal (4-HNE), a major aldehyde derived from lipid peroxidation of n-6 polyunsaturated fatty acids trigger signals that modulates focal adhesion and adherens junction proteins thereby inducing endothelial barrier dysfunction. Similarly, oxidized phospholipids (Ox-PLs) generated by lipid peroxidation of phospholipids with polyunsaturated fatty acids have been implicated in atherogenesis, inflammation and gene expression. Interestingly, physiological concentration of Ox-PLs is anti-inflammatory and protect against endotoxin- and ventilator-associated acute lung injury. Thus, excess generation of bioactive hydroxyalkenals and Ox-PLs during oxidative stress contributes to pathophysiology of various diseases by modulating signaling pathways that regulate pro- and anti-inflammatory responses and barrier regulation. This review summarizes the role of 4-HNE and Ox-PLs affecting cell signaling pathways and endothelial barrier dysfunction through modulation of the activities of proteins/enzymes by Michael adducts formation, enhancing the level of protein tyrosine phosphorylation of the target proteins, and by reorganization of cytoskeletal, focal adhesion, and adherens junction proteins. A better understanding of molecular mechanisms of hydroxyalkenals- and Ox-PLs-mediated pro-and anti-inflammatory responses and barrier function may lead to development of novel therapies to ameliorate oxidative stress related cardio-pulmonary disorders.
    Microvascular Research 05/2011; 83(1):45-55. DOI:10.1016/j.mvr.2011.04.012 · 2.13 Impact Factor
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    • "αvβ5 and/or αvβ6) other than αvβ5 is likely to be responsible for the protective effects of RGDS on BAL protein accumulation. Indeed, a blocking antibody against the integrin αvβ5 or αvβ6 protected development of lung vascular permeability in different models of acute lung injury [35-37]. Additional studies are required to identify a physiological role of β3 integrin in the development of pulmonary edema during acute lung injury. "
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    ABSTRACT: Synthetic peptides containing the RGD sequence inhibit integrin-related functions in different cell systems. Here, we investigated the effects of synthetic Arg-Gly-Asp-Ser (RGDS) peptide on key inflammatory responses to intratracheal (i.t.) lipopolysaccharide (LPS) treatment and on the integrin signaled mitogen-activated protein (MAP) kinase pathway during the development of acute lung injury. Saline or LPS (1.5 mg/kg) was administered i.t. with or without a single dose of RGDS (1, 2.5, or 5 mg/kg, i.p.), anti-alphav or anti-beta3 mAb (5 mg/kg, i.p.). Mice were sacrificed 4 or 24 h post-LPS. A pretreatment with RGDS inhibited LPS-induced increases in neutrophil and macrophage numbers, total protein levels and TNF-alpha and MIP-2 levels, and matrix metalloproteinase-9 activity in bronchoalveolar lavage (BAL) fluid at 4 or 24 h post-LPS treatment. RGDS inhibited LPS-induced phosphorylation of focal adhesion kinase and MAP kinases, including ERK, JNK, and p38 MAP kinase, in lung tissue. Importantly, the inhibition of the inflammatory responses and the kinase pathways were still evident when this peptide was administered 2 h after LPS treatment. Similarly, a blocking antibody against integrin alphav significantly inhibited LPS-induced inflammatory cell migration into the lung, protein accumulation and proinflammatory mediator production in BAL fluid, at 4 or 24 h post-LPS. Anti-beta3 also inhibited all LPS-induced inflammatory responses, except the accumulation of BAL protein at 24 h post-LPS. These results suggest that RGDS with high specificity for alphavintegrins attenuates inflammatory cascade during LPS-induced development of acute lung injury.
    Respiratory research 02/2009; 10(1):18. DOI:10.1186/1465-9921-10-18 · 3.09 Impact Factor
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