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Hypoxia-Induced Mitogenic Factor Has Antiapoptotic Action and Is Upregulated in the Developing Lung

Coexpression with Hypoxia-Inducible Factor-2

Departments of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; and Department of Physiology, University Lübeck, Lübeck, Germany

Address correspondence to: Dechun Li, M.D., Ph.D., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 600 N. Wolfe St., Blalock 1404A, Baltimore, MD 21287. E-mail: dechunli{at}jhmi.edu

Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELM, was a newly found cytokine. Hypoxia caused robust HIMF induction in the lung, and HIMF has potent pulmonary vasoconstrictive, proliferative, and angiogenic properties. To investigate the role of HIMF in lung development, we determined its spatial and temporal expression. From embryonic day (E)16 to postnatal day (P)28, HIMF was strongly expressed in the cytoplasm of bronchial epithelial cells, type II cells, endothelial cells, and primitive mesenchymal cells. Treatment with HIMF resulted in a significant reduction of apoptosis in cultured embryonic lung, thus revealing a previously unknown function of HIMF. Because HIMF gene is upregulated by hypoxia and contains a hypoxia-inducible transcription factor (HIF) binding site, we subsequently investigated whether HIMF was coexpressed with HIF-2 or HIF-1. HIF-1 expression was temporally distinct from HIMF expression. In contrast, HIF-2 was present in endothelial cells, bronchial epithelial cells, and type II cells from E18 to P28. Thus, HIMF and HIF-2 were temporally and spatially coexpressed in the developing lung. These results indicate a role for HIMF in lung development, possibly under the control of HIF-2, and suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation.

Abbreviations: diaminobenzidine, DAB • hypoxia-inducible transcription factor, HIF • hypoxia-induced mitogenic factor, HIMF • horseradish peroxidase, HRP • phosphate-buffered saline, PBS • sodium dodecylsulfate, SDS • saline sodium citrate, SSC

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