Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha

Am J Respir Cell Mol Biol. 2004 Sep;31(3):276-82. doi: 10.1165/rcmb.2003-0319OC. Epub 2004 Apr 29.


Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELMalpha, 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-2alpha or HIF-1alpha. HIF-1alpha expression was temporally distinct from HIMF expression. In contrast, HIF-2alpha was present in endothelial cells, bronchial epithelial cells, and type II cells from E18 to P28. Thus, HIMF and HIF-2alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Basic Helix-Loop-Helix Transcription Factors
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Fetus
  • Gene Expression Regulation, Developmental / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins
  • Lung / blood supply
  • Lung / cytology
  • Lung / embryology*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / genetics
  • Neovascularization, Physiologic / physiology*
  • Nerve Growth Factor / genetics*
  • Nerve Growth Factor / metabolism*
  • Nerve Growth Factor / pharmacology
  • Proteins*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Up-Regulation / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Retnla protein, mouse
  • Trans-Activators
  • Transcription Factors
  • endothelial PAS domain-containing protein 1
  • Nerve Growth Factor