Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension

Olga Rafikova, Elissa R. Williams, Matthew L. McBride, Marina Zemskova, Anup Srivastava, Vineet Nair, Ankit Desai, Paul R. Langlais, Evgeny Zemskov, Marc Simon, Lawrence J. Mandarino, Ruslan Rafikov

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12 Scopus citations

Abstract

Although hemolytic anemia-associated pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are more common than the prevalence of idiopathic PAH alone, the role of hemolysis in the development of PAH is poorly characterized. We hypothesized that hemolysis independently contributes to PAH pathogenesis via endothelial barrier dysfunction with resulting perivascular edema and inflammation. Plasma samples from patients with and without PAH (both confirmed by right heart catheterization) were used to measure free hemoglobin (Hb) and its correlation with PAH severity. A sugen (50 mg/kg)/hypoxia (3 wk)/normoxia (2 wk) rat model was used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells were used to study heme-mediated endothelial barrier effects. Our data indicate that patients with PAH have increased levels of free Hb in plasma that correlate with PAH severity. There is also a significant accumulation of free Hb and depletion of haptoglobin in the rat model. In rats, perivascular edema was observed at early time points concomitant with increased infiltration of inflammatory cells. Heme-induced endothelial permeability in human lung microvascular endothelial cells involved activation of the p38/HSP27 pathway. Indeed, the rat model also exhibited increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling, there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF-1a during the first 2 weeks of PH regardless of hypoxic conditions. Our data suggest that hemolysis may play a significant role in PAH pathobiology.

Original languageEnglish (US)
Pages (from-to)334-345
Number of pages12
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume59
Issue number3
DOIs
StatePublished - Sep 1 2018

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Keywords

  • Edema
  • Endothelial barrier
  • Heme
  • Hemoglobin
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Rafikova, O., Williams, E. R., McBride, M. L., Zemskova, M., Srivastava, A., Nair, V., Desai, A., Langlais, P. R., Zemskov, E., Simon, M., Mandarino, L. J., & Rafikov, R. (2018). Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology, 59(3), 334-345. https://doi.org/10.1165/rcmb.2017-0308OC