Journal
CIRCULATION
Volume 128, Issue 12, Pages 1354-1364Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.003072
Keywords
hypertension; pulmonary; schistosomiasis; transforming growth factor beta
Funding
- Pfizer Advancing Science Through Pfizer Investigator-Research Exchange grants
- Flight Attendant Medical Research Institute [092054_CIA]
- Cardiovascular Medical Research and Education Fund
- National Institutes of Health [RC1HL100849, K08HL105536]
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Background The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor- (TGF-) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. Methods and Results Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for approximate to 60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF- signaling, as pharmacological blockade of the TGF- ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF- signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF- signaling in their remodeled pulmonary arteries. Conclusion Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF- signaling.
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