Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut-lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression.
Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut-lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression.
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血吸虫病相关肺动脉高压揭示小鼠肠道 - 肺微生物组紊乱以及内源性保护蛋白小窝蛋白 - 1/骨形态发生蛋白受体2（Caveolin - 1/BMPR2）表达降低。
DOI：
10.3389/fimmu.2023.1254762
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发表时间：
2023
影响因子：
7.3
通讯作者：
Oliveira, Suellen D.
中科院分区：
文献类型：
--
作者：
Marinho, Ygor;Villarreal, Elizabeth S.;Aboagye, Sammy Y.;Williams, David L.;Sun, Jun;Silva, Claudia L. M.;Lutz, Sarah E.;Oliveira, Suellen D.
血吸虫病相关肺动脉高压（Sch-PAH）是慢性曼氏梭菌感染的一种危及生命的并发症，可导致心力衰竭和死亡。在PAH期间，凋亡抵抗内皮细胞（ECs）的扩张已被广泛报道；然而，预防这种病理表型进展或逆转的治疗方法在临床上仍然具有挑战性。先前，我们发现细胞外囊泡脱落导致抗凋亡蛋白Cav-1 （Cav-1）的消耗有助于将内源性保护性骨形态发生蛋白受体2 （BMPR2）转向转化生长因子β (TGF-β)介导的异常EC表型的存活。然而，PAH内源性保护功能降低的机制尚不清楚。有趣的是，最近的研究结果表明，与肠道相似，健康的人类肺部也有多种微生物群，它们的组成在很大程度上取决于包括感染在内的内在和外在宿主因素。尽管目前已知肠道微生物群的破坏有助于多环芳烃的发展，但肺微生物群的作用仍不清楚。因此，使用Sch-PAH的临床前动物模型，我们测试了曼氏梭菌感染是否会改变肠道-肺微生物组组成并导致EC损伤，从而启动PAH中观察到的异常EC表型的扩展。事实上，曼氏梭菌卵的体内刺激除了促进肺血管损伤外，还显著改变了肠道-肺微生物组谱，其特征是凋亡标志物增加，肺Cav-1和BMPR2的内源性保护性表达减少。此外，mansoni卵刺激引起严重的肺血管重构，导致右心室收缩压升高和肥厚，这是PAH的特征。在体外，暴露于免疫优势的mansoni S. egg抗原p40激活了TLR4/ cd14介导的人肺微血管EC （HMVEC-L）中Cav-1 Tyr14位点的短暂磷酸化，最终导致Cav-1表达轻度降低，但未能促进体内观察到的细胞外囊泡的死亡和脱落。总之，这些数据表明，宿主相关的肠道-肺微生物群的破坏可能是PAH中观察到的异常肺内皮表型的出现和扩大所必需的，除了曼氏梭菌卵和抗原。
Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic S. mansoni infection that can lead to heart failure and death. During PAH, the expansion of apoptosis-resistant endothelial cells (ECs) has been extensively reported; however, therapeutic approaches to prevent the progression or reversal of this pathological phenotype remain clinically challenging. Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) by shedding extracellular vesicles contributes to shifting endoprotective bone morphogenetic protein receptor 2 (BMPR2) towards transforming growth factor beta (TGF-β)-mediated survival of an abnormal EC phenotype. However, the mechanism underlying the reduced endoprotection in PAH remains unclear. Interestingly, recent findings indicate that, similar to the gut, healthy human lungs are populated by diverse microbiota, and their composition depends significantly on intrinsic and extrinsic host factors, including infection. Despite the current knowledge that the disruption of the gut microbiome contributes to the development of PAH, the role of the lung microbiome remains unclear. Thus, using a preclinical animal model of Sch-PAH, we tested whether S. mansoni infection alters the gut–lung microbiome composition and causes EC injury, initiating the expansion of an abnormal EC phenotype observed in PAH. Indeed, in vivo stimulation with S. mansoni eggs significantly altered the gut–lung microbiome profile, in addition to promoting injury to the lung vasculature, characterized by increased apoptotic markers and loss of endoprotective expression of lung Cav-1 and BMPR2. Moreover, S. mansoni egg stimulus induced severe pulmonary vascular remodeling, leading to elevated right ventricular systolic pressure and hypertrophy, characteristic of PAH. In vitro, exposure to the immunodominant S. mansoni egg antigen p40 activated TLR4/CD14-mediated transient phosphorylation of Cav-1 at Tyr14 in human lung microvascular EC (HMVEC-L), culminating in a mild reduction of Cav-1 expression, but failed to promote death and shedding of extracellular vesicles observed in vivo. Altogether, these data suggest that disruption of the host-associated gut–lung microbiota may be essential for the emergence and expansion of the abnormal lung endothelial phenotype observed in PAH, in addition to S. mansoni eggs and antigens.
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影响因子：
3.3
作者：
Chen Z;D S Oliveira S;Zimnicka AM;Jiang Y;Sharma T;Chen S;Lazarov O;Bonini MG;Haus JM;Minshall RD
通讯作者：
Minshall RD
影响因子：
4.6
作者：
Holzscheiter, M.;Layland, L. E.;da Costa, C. Prazeres
通讯作者：
da Costa, C. Prazeres
影响因子：
37.8
作者：
Hopper RK;Moonen JR;Diebold I;Cao A;Rhodes CJ;Tojais NF;Hennigs JK;Gu M;Wang L;Rabinovitch M
通讯作者：
Rabinovitch M
影响因子：
4.6
作者：
Callejo M;Mondejar-Parreño G;Barreira B;Izquierdo-Garcia JL;Morales-Cano D;Esquivel-Ruiz S;Moreno L;Cogolludo Á;Duarte J;Perez-Vizcaino F
通讯作者：
Perez-Vizcaino F
影响因子：
16.6
作者：
Kumar R;Mickael C;Kassa B;Gebreab L;Robinson JC;Koyanagi DE;Sanders L;Barthel L;Meadows C;Fox D;Irwin D;Li M;McKeon BA;Riddle S;Dale Brown R;Morgan LE;Evans CM;Hernandez-Saavedra D;Bandeira A;Maloney JP;Bull TM;Janssen WJ;Stenmark KR;Tuder RM;Graham BB
通讯作者：
Graham BB