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

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.

Antibody response to Merkel cell polyomavirus associated with incident lymphoma in the Epilymph case-control study in Spain.

BACKGROUND: Merkel cell polyomavirus (MCV) has been identified as the cause of Merkel cell carcinoma. The increased incidence of chronic lymphocytic leukemia in Merkel cell cancer cohorts and the lymphotropic properties of the virus suggest a possible viral association with lymphomagenesis. To investigate this potential role, we explored seroreactivity against MCV VP1 capsids within the Epilymph case-control study in Spain. METHODS: Serum samples from 468 incident lymphomas, categorized into up to 11 entities, and 522 controls frequency matched by age, sex, and recruitment center were tested for MCV antibodies by enzyme immunoassay using Virus-Like-Particles. Adjusted multinomial logistic regression was used to estimate the OR and 95% confidence interval (CI) associated to MCV seroprevalence. Immunosuppressed subjects were excluded. RESULTS: MCV seroprevalence was 82% in controls and 85% in lymphoma cases. Among 11 lymphoma categories, MCV seropositivity was significantly higher in diffuse large B-cell lymphomas (DLBCL; 96.4%; OR = 6.1, 95%CI = 1.9-19.8), as compared with controls. MCV prevalences were also higher in follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, and mature T-cell lymphoma but differences did not reach statistical significance. Lower prevalences were observed for multiple myeloma and other B-cell lymphoma. Exclusion of samples collected after start of treatment did not change the results. In a subset analysis, no significant association was observed between BKV and JCV seroprevalence and DLBCL. CONCLUSION: The association observed between serologic evidence of MCV exposure and DLBCL warrants further research. IMPACT: MCV might be involved in the pathway of DLBCL and other lymphomas.