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Inhibition of CXCR₂ attenuates bronchial angiogenesis in the ischemic rat lung

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland

Submitted 14 September 2007 ; accepted in final form 1 March 2008

Under conditions of chronic pulmonary ischemia, the bronchial circulation undergoes massive proliferation. However, little is known regarding the mechanisms that promote neovascularization. An expanding body of literature implicates the glutamic acid-leucine-arginine (ELR+) CXC chemokines and their G protein-coupled receptor, CXCR₂, as key proangiogenic components in the lung. We used a rat model of chronic pulmonary ischemia induced by left pulmonary artery ligation (LPAL) to study bronchial angiogenesis. Using a methacrylate mixture, we cast the systemic vasculature of the rat lung at weekly intervals after LPAL. Twenty-one days after LPAL, numerous large, tortuous bronchial arteries were observed surrounding the left main bronchus that penetrated the left lung parenchyma. In stark contrast, the right lung was essentially devoid of vessels. We quantified bronchial neovascularization using 15-µm radiolabeled microspheres to measure systemic blood flow to the left lung (n = 12 rats). Results showed that by 21 days after LPAL, bronchial blood flow to the ischemic left lung had increased >10-fold compared with controls 2 days after LPAL (P < 0.01). Focusing on the predominant rat CXC chemokine that signals through CXCR₂, we measured increased levels of cytokine-induced neutrophil chemoattractant-3 protein expression in left lung homogenates early (4 and 24 h; n = 10 rats) after LPAL relative to paired right lung controls (P < 0.01). Treatment with a neutralizing antibody to CXCR₂ resulted in a significant decrease in neovascularization 21 days after LPAL (n = 9 rats; P < 0.01). Our results confirm the time course of bronchial angiogenesis in the rat and suggest the importance of CXC chemokines in promoting systemic neovascularization in the lung.

bronchial artery; cytokine-induced neutrophil chemoattractant-3; microspheres