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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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

Fingerprint

Hemolysis
Heme
Pulmonary Hypertension
Blood Vessels
Rats
Hemoglobins
Lung
Chemical activation
Endothelial cells
Plasmas
Heme Oxygenase-1
Haptoglobins
Infiltration
Edema
Endothelial Cells
Hemolytic Anemia
Cardiac Catheterization
Permeability
Inflammation

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., ... 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

Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension. / Rafikova, Olga; Williams, Elissa R.; McBride, Matthew L.; Zemskova, Marina; Srivastava, Anup; Nair, Vineet; Desai, Ankit; Langlais, Paul R.; Zemskov, Evgeny; Simon, Marc; Mandarino, Lawrence J.; Rafikov, Ruslan.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 59, No. 3, 01.09.2018, p. 334-345.

Research output: Contribution to journalArticle

Rafikova, O, Williams, ER, McBride, ML, Zemskova, M, Srivastava, A, Nair, V, Desai, A, Langlais, PR, Zemskov, E, Simon, M, Mandarino, LJ & Rafikov, R 2018, 'Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension', American Journal of Respiratory Cell and Molecular Biology, vol. 59, no. 3, pp. 334-345. https://doi.org/10.1165/rcmb.2017-0308OC
Rafikova, Olga ; Williams, Elissa R. ; McBride, Matthew L. ; Zemskova, Marina ; Srivastava, Anup ; Nair, Vineet ; Desai, Ankit ; Langlais, Paul R. ; Zemskov, Evgeny ; Simon, Marc ; Mandarino, Lawrence J. ; Rafikov, Ruslan. / Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension. In: American Journal of Respiratory Cell and Molecular Biology. 2018 ; Vol. 59, No. 3. pp. 334-345.
@article{5be2aa7037f9450fa6ed37ca5b07dfe6,
title = "Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension",
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.",
keywords = "Edema, Endothelial barrier, Heme, Hemoglobin, Pulmonary arterial hypertension",
author = "Olga Rafikova and Williams, {Elissa R.} and McBride, {Matthew L.} and Marina Zemskova and Anup Srivastava and Vineet Nair and Ankit Desai and Langlais, {Paul R.} and Evgeny Zemskov and Marc Simon and Mandarino, {Lawrence J.} and Ruslan Rafikov",
year = "2018",
month = "9",
day = "1",
doi = "10.1165/rcmb.2017-0308OC",
language = "English (US)",
volume = "59",
pages = "334--345",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "3",

}

TY - JOUR

T1 - Hemolysis-induced lung vascular leakage contributes to the development of pulmonary hypertension

AU - Rafikova, Olga

AU - Williams, Elissa R.

AU - McBride, Matthew L.

AU - Zemskova, Marina

AU - Srivastava, Anup

AU - Nair, Vineet

AU - Desai, Ankit

AU - Langlais, Paul R.

AU - Zemskov, Evgeny

AU - Simon, Marc

AU - Mandarino, Lawrence J.

AU - Rafikov, Ruslan

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - Edema

KW - Endothelial barrier

KW - Heme

KW - Hemoglobin

KW - Pulmonary arterial hypertension

UR - http://www.scopus.com/inward/record.url?scp=85052827745&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052827745&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2017-0308OC

DO - 10.1165/rcmb.2017-0308OC

M3 - Article

C2 - 29652520

AN - SCOPUS:85052827745

VL - 59

SP - 334

EP - 345

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 3

ER -