Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

Daniel J Angelini,Chunling Fan,Roger A Johns,Chris Cheadle,Kazuyo Yamaji-Kegan,Hazim El-Haddad,Qingning Su,John T Skinner,Andre Poloczek

doi:10.1186/1465-9921-14-1

Daniel J Angelini, Chunling Fan + Show 7 more

Open Access

https://doi.org/10.1186/1465-9921-14-1

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Abstract

BackgroundBoth 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.MethodsWe 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.ResultsChronic 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.ConclusionsThe 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.

Highlights

Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause Pulmonary hypertension (PH)
The current study demonstrates that both chronic hypoxia and repeated airway antigen challenges induce pulmonary vascular remodeling in adult male C57BL/6 mice; differences were apparent in the types and extent of remodeling
Exposure to chronic hypoxia for 28 days increased all of the indicators of PH that we examined in this study [mean pulmonary artery pressure (mPAP), right ventricle (RV)/(LV+S) ratio, vascular remodeling]

Summary

Introduction

Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. Swain et al [17] reported pulmonary vascular remodeling and development of PH as a result of Pneumocystis pneumonia in both wild-type and CD4+ T-cell-depleted mice; notably, these pathological changes still occurred in IL-4 knockout mice, and IL-13 was not detected in the lungs of the mice during the persistent phase of the model [17] These studies suggest a role for inflammation in pulmonary vascular remodeling, but currently, the exact involvement in this process is unclear

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