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IL-4 Is Proangiogenic in the Lung under Hypoxic Conditions¹

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205

IL-4-mediated proangiogenic and proinflammatory vascular responses have been implicated in the pathogenesis of chronic lung diseases such as asthma. Although it is well known that hypoxia induces pulmonary angiogenesis and vascular alterations, the underlying mechanism of IL-4 on the pulmonary vasculature under hypoxic conditions remains unknown. In this context, we designed the present study to determine the functional importance of IL-4 for pulmonary angiogenesis under hypoxic conditions using IL-4 knockout (KO) animals. Our results show that hypoxia significantly increased IL-4R expression in wild-type (WT) control lungs. Even though hypoxia significantly up-regulated vascular endothelial growth factor (VEGF) receptor expression in the lungs of both genotypes, hypoxia-induced VEGF, VCAM-1, HIF-1, and ERK phosphorylation were significantly diminished in IL-4 KO lungs as compared with WT control lungs. In addition, hypoxia-induced pulmonary angiogenesis and proliferating activities in the airway and pulmonary artery were significantly suppressed in IL-4 KO lungs as compared with WT control lungs. We also isolated primary lung fibroblasts from these genotypes and stimulated these cells with hypoxia. Hypoxia-induced VEGF production was significantly suppressed in lung fibroblasts from IL-4 KO mice. These in vitro results are in accordance with the in vivo data. Furthermore, we observed a significant increase of hypoxia-induced pulmonary angiogenesis in STAT6 KO mice similar to that in WT controls. In conclusion, IL-4 has proangiogenic properties in the lung under hypoxic conditions via the VEGF pathway, and this is independent of the STAT6 pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health (NIH) Grant RO1 39706 (to R.A.J.) and NIH Specialized Centers of Clinically Oriented Research Grant P50 084946 (to R.A.J.).

² Address correspondence and reprint requests to Dr. Roger A. Johns, Ross 361, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205. E-mail address: rjohns2{at}jhmi.edu

³ Abbreviations used in this paper used in this paper: VEGF, vascular endothelial growth factor; EC, endothelial cell; HIF, hypoxia inducible factor; KO, knockout; PCNA, proliferating cell nuclear Ag; SMC, smooth muscle cell; VE-cadherin, vascular endothelium cadherin; VEGFR, VEGF receptor; vWF, Von Willebrand factor; WT, wild type.