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 language | English (US) |
|---|---|
| Pages (from-to) | 334-345 |
| Number of pages | 12 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 59 |
| Issue number | 3 |
| DOIs | |
| State | Published - 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
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 journal › Article
}
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 -