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Published on: August 2, 2018
Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular
Daniel J Angelini1, Qingning Su, Kazuyo Yamaji-Kegan
1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Background:
Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and role of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in explaining this differential response.
Methods:
We induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and challenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung vascular bed as well as HIMF expression and genomic analysis of whole lung.
Results:
Chronic hypoxia increased both mean pulmonary artery pressure (mPAP) and right ventricular (RV) hypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary vessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and produced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung periphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently upregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the airway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in vascular tissue.
Conclusions:
The results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen challenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of the lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the failure to develop PH in the allergic inflammation model.
Insights
Chronic hypoxia causes pulmonary hypertension (PH) and vascular remodeling, unlike allergic inflammation. Hypoxia-induced mitogenic factor (HIMF) upregulation in lung vasculature explains this difference, preventing PH in allergic models.
Area of Science:
- Pulmonary Hypertension Research
- Vascular Biology
- Immunology
Background:
- Both chronic hypoxia and allergic inflammation can cause lung vascular remodeling.
- However, only chronic hypoxia typically leads to pulmonary hypertension (PH).
- The differential response and the role of hypoxia-induced mitogenic factor (HIMF) require investigation.
Purpose of the Study:
- To investigate the distinct vascular remodeling patterns induced by chronic hypoxia versus allergic inflammation.
- To examine the expression and role of HIMF in explaining the development of PH.
- To understand why allergic inflammation does not cause PH despite vascular changes.
Main Methods:
- Pulmonary vascular remodeling was induced in mice using chronic hypoxia or antigen sensitization and challenge.
- Mice were assessed for PH markers, vascular remodeling, HIMF expression, and genomic changes.
- Analysis focused on the entire lung vascular bed and specific cell types.
Main Results:
- Chronic hypoxia increased pulmonary artery pressure and right ventricular hypertrophy, with widespread small vessel muscularization.
- Allergic inflammation caused minimal PH markers and limited peribronchial vessel thickening.
- HIMF was upregulated in both models but only in vascular tissue during chronic hypoxia.
Conclusions:
- Pulmonary vascular remodeling in both models correlates with increased HIMF expression.
- Lack of HIMF in lung vasculature and peripheral vessels explains the absence of PH in allergic inflammation.
- Differential HIMF expression in vascular tissue is key to understanding PH development.
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