Transpulmonary generation of cell-free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms.
Transpulmonary generation of cell-free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms.
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DOI：
10.1002/pul2.12185
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发表时间：
2023-01
影响因子：
2.6
通讯作者：
Brittain, Evan L.
中科院分区：
文献类型：
--
作者：
Meegan, Jamie E.;Kerchberger, Vern Eric;Fortune, Niki L.;McNeil, Joel Brennan;Bastarache, Julie A.;Austin, Eric D.;Ware, Lorraine B.;Hemnes, Anna R.;Brittain, Evan L.
肺动脉高压（PAH）时循环游离血红蛋白（CFH）升高，并与不良预后相关，但其机制尚不清楚。我们假设 CFH 是由肺循环产生的，而 PAH 中的清除不充分。对 PAH 患者和健康对照者的经肺 CFH（楔形动脉和肺动脉位置之间的差异）和肺血红蛋白 α 进行了分析。对 PAH 患者、未受影响的骨形态发生蛋白受体 II 型突变携带者 (UMC) 和对照受试者的触珠蛋白基因型和血浆血红蛋白加工蛋白进行了分析。 PAH 患者的跨肺 CFH 增加 (p = 0.04)，并与肺血管阻力 (PVR) (r s = 0.75，p = 0.02) 和平均肺动脉压 (mPAP) (r s = 0.78，p = 0.02) 相关。 PAH 患者的肺血管血红蛋白 α 蛋白升高 (p = 0.006)，尤其是闭塞血管 (p = 0.04)。触珠蛋白基因型在各组之间没有差异。与对照受试者 (p = 0.03) 和 HPAH 患者 (p < 0.0001) 相比，UMC 的血浆触珠蛋白较高； IPAH 患者的循环触珠蛋白水平高于 HPAH 患者 (p = 0.006)。值得注意的是，与对照受试者 (p = 0.02) 和 UMC (p = 0.006) 相比，HPAH 患者的循环 CFH 与触珠蛋白比率升高。此外，在 PAH 患者中，CFH：触珠蛋白与 PVR（rs = 0.37，p = 0.0004）和 mPAP（rs = 0.25，p = 0.02）相关。观察到其他血浆血红蛋白加工蛋白（血红素结合蛋白、血红素加氧酶-1 和 sCD163）的广泛变化。总之，肺血管 CFH 与 PAH 中 PVR 和 mPAP 增加相关，CFH 清除失调可能导致 PAH 病理。需要进一步的研究来确定靶向 CFH 是否是治疗 PAH 肺血管功能障碍的可行疗法。
Circulating cell‐free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemoglobin α were analyzed in patients with PAH and healthy controls. Haptoglobin genotype and plasma hemoglobin processing proteins were analyzed in patients with PAH, unaffected bone morphogenetic protein receptor type II mutation carriers (UMCs), and control subjects. Transpulmonary CFH was increased in patients with PAH (p = 0.04) and correlated with pulmonary vascular resistanc (PVR) (r s = 0.75, p = 0.02) and mean pulmonary arterial pressure (mPAP) (r s = 0.78, p = 0.02). Pulmonary vascular hemoglobin α protein was increased in patients with PAH (p = 0.006), especially in occluded vessels (p = 0.04). Haptoglobin genotype did not differ between groups. Plasma haptoglobin was higher in UMCs compared with both control subjects (p = 0.03) and patients with HPAH (p < 0.0001); patients with IPAH had higher circulating haptoglobin levels than patients with HPAH (p = 0.006). Notably, circulating CFH to haptoglobin ratio was elevated in patients with HPAH compared to control subjects (p = 0.02) and UMCs (p = 0.006). Moreover, in patients with PAH, CFH: haptoglobin correlated with PVR (r s = 0.37, p = 0.0004) and mPAP (r s = 0.25, p = 0.02). Broad alterations in other plasma hemoglobin processing proteins (hemopexin, heme oxygenase‐1, and sCD163) were observed. In conclusion, pulmonary vascular CFH is associated with increased PVR and mPAP in PAH and dysregulated CFH clearance may contribute to PAH pathology. Further study is needed to determine whether targeting CFH is a viable therapeutic for pulmonary vascular dysfunction in PAH.
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影响因子：
30.8
作者：
Boettger, Linda M.;Salem, Rany M.;McCarroll, Steven A.
通讯作者：
McCarroll, Steven A.
影响因子：
20.3
作者：
Lim, SK;Kim, HK;Baumman, H
通讯作者：
Baumman, H
影响因子：
20.3
作者：
Hsu, Lewis L.;Champion, Hunter C.;Gladwin, Mark T.
通讯作者：
Gladwin, Mark T.
影响因子：
9.6
作者：
Brittain, Evan L.;Janz, David R.;Hemnes, Anna R.
通讯作者：
Hemnes, Anna R.
DOI：
10.1016/j.bbrc.2021.03.161
发表时间：
2021-06-04
影响因子：
3.1
作者：
Tomasek T;Ware LB;Bastarache JA;Meegan JE
通讯作者：
Meegan JE