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CA (carbonic anhydrase) IX is expressed in pulmonary microvascular endothelial cells (PMVECs), where it contributes to CO2 and pH homeostasis, bioenergetics, and angiogenesis. We hypothesized that CA IX is important for PMVEC survival and that CA IX expression and release from PMVECs are increased during infection. Although the plasma concentration of CA IX was unchanged in human and rat pneumonia, there was a trend toward increasing CA IX in the bronchoalveolar fluid of mechanically ventilated critically ill patients with pneumonia and a significant increase in CA IX in the lung tissue lysates of pneumonia rats. To investigate the functional implications of the lung CA IX increase, we generated PMVEC cell lines harboring domain-specific CA IX mutations. By using these cells, we found that infection promotes intracellular (IC) expression, release, and MMP (metalloproteinase)-mediated extracellular cleavage of CA IX in PMVECs. IC domain deletion uniquely impaired CA IX membrane localization. Loss of the CA IX IC domain promoted cell death after infection, suggesting that the IC domain has an important role in PMVEC survival. We also found that hypoxia improves survival, whereas hypercapnia reverses the protective effect of hypoxia, during infection. Thus, we report 1) that CA IX increases in the lungs of pneumonia rats and 2) that the CA IX IC domain and hypoxia promote PMVEC survival during infection.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0537oc","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T11:01:01Z","timestamp":1626087661000},"page":"630-645","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":6,"title":["Carbonic Anhydrase IX and Hypoxia Promote Rat Pulmonary Endothelial Cell Survival during Infection"],"prefix":"10.1093","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-2446","authenticated-orcid":false,"given":"Ji Young","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Physiology and Cell Biology, and"},{"name":"Department of Internal Medicine"},{"name":"Division of Pulmonary and Critical Care Medicine"},{"name":"Center for Lung Biology"},{"name":"College of Medicine, University of 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