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

Abstract

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.

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

“…HIF1␣ is the most widely expressed of the tightly regulated ␣-subunits, whereas HIF2␣ expression varies significantly among cell types; in the mature lung, HIF1␣ is expressed ubiquitously in tissues exposed to hypoxia, whereas HIF2␣ expression is restricted specifically to the ATII cells and vascular endothelium (39). Work in the lung has shown that HIF1␣ can drive hypoxia-induced apoptosis in ATII cells (11,18), whereas other studies have shown that HIF2␣ plays a critical role in regulating production of pulmonary surfactant (1), as well as roles in alveolar development (16) and promoting antiapoptosis pathways (38). Considerable cross-regulation between isoforms has been suggested; for example, HIF2␣ expression is abrogated in lung-targeted HIF1␣ knockouts, and HIF2␣ activation may be dependent on initial HIF1␣ signaling (15,32).…”

Human RELMβ is a mitogenic factor in lung cells and induced in hypoxia

“…Beside proliferative effects, HIMF was demonstrated to have angiogenic (subcutaneous mouse in vivo matrigel plug model) and vasoconstrictive properties in pulmonary artery [3]. In addition, HIMF was shown to play a role in lung development, by regulation of apoptosis and participation in alveolarization and lung maturation [9] and compensatory lung growth after pneumectomy [10]. Also, HIMF (FIZZ1) was shown to be strongly increased during allergic pulmonary inflammation [6].…”

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

“…There are three other rodent members of this gene family that are known as RELM-b/FIZZ2/ mXCP3, resistin/FIZZ3/mXCP4, and RELM-g/FIZZ4/mXCP1. We reported previously that HIMF expression is increased in the lungs of chronically hypoxic mice (15) and in the normal developing murine lung (21). We have also shown that HIMF introduced into murine lung induces angiogenesis and vascular thickening (22).…”

“…Previous studies from our laboratory have shown that recombinant HIMF has mitogenic, angiogenic, and vasoconstrictive effects in lung (15), and that HIMF possesses an antiapoptotic function in cultured murine embryonic lungs (21). It also has been reported that HIMF plays a role in type 2 T helper cell (Th)-mediated inflammation.…”