Bronchoconstriction damages airway epithelia by excess crowding-induced extrusion
Bronchoconstriction damages airway epithelia by excess crowding-induced extrusion
复制标题
过度拥挤引起的挤压会导致支气管收缩损伤气道上皮
DOI：
10.1101/2023.08.04.551943
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Bagley D
中科院分区：
文献类型：
--
作者：
Bagley D
哮喘是一种常见的疾病，其特征是气道收缩、粘液过多和炎症。虽然哮喘是一种炎症性疾病，可根据不同的内型、触发因素和免疫反应进行细分，但其定义性诊断症状是平滑肌收缩不受控制引起的机械性支气管收缩。我们以前发现了一个保守的过程，驱动上皮细胞死亡的机械细胞拥挤称为上皮细胞挤压，。由于适度的拥挤会引发挤出以维持恒定的稳态上皮细胞密度，我们推断支气管收缩引起的病理性拥挤可能会破坏气道上皮屏障，导致哮喘发作后的典型炎症期。在这里，使用免疫致敏小鼠，我们表明支气管收缩的拥挤导致过度的上皮细胞挤出和损伤，导致远端气道炎症和近端气道粘液分泌。令人惊讶的是，用目前的补救治疗沙丁胺醇放松支气管收缩后的气道，并不能防止上皮挤出和破坏、炎症或粘液分泌。然而，使用牵张激活/TRP通道或1-磷酸鞘氨醇（S1 P）抑制剂抑制支气管收缩期间的典型活细胞挤出信号传导可以阻止所有下游症状。我们的研究结果提出了一种新的哮喘病因，即支气管收缩性发作引起的极端机械性拥挤通过损伤气道上皮引起炎症。虽然大多数治疗方法都集中在调节下游炎症症状，但我们的研究表明，阻断上皮细胞的挤出可以防止前馈哮喘炎症循环。
Asthma is a common disease characterized by airway constriction, excess mucus, and inflammation. Although asthma is an inflammatory disease, subclassed by different endotypes, triggers, and immune responses, the defining diagnostic symptom is mechanical bronchoconstriction from uncontrolled smooth muscle contraction. We previously discovered a conserved process that drives epithelial cell death in response to mechanical cell crowding called epithelial cell extrusion,. Because modest crowding triggers extrusion to maintain constant homeostatic epithelial cell densities, we reasoned that the pathological crowding from bronchoconstriction might potentially destroy the airway epithelial barrier, causing the typical inflammatory period that follows an asthma attack. Here, using immune-primed mice, we show that the crowding of bronchoconstriction causes excess epithelial cell extrusion and damage, resulting in inflammation in distal airways, and mucus secretion in proximal airways. Surprisingly, relaxing airways following bronchoconstriction with the current rescue treatment, albuterol, did not prevent epithelial extrusion and destruction, inflammation, or mucus secretion. However, inhibiting canonical live cell extrusion signaling during bronchoconstriction with stretch-activated/TRP channel or sphingosine 1-phosphate (S1P) inhibitors blocked all downstream symptoms. Our findings propose a new etiology for asthma where the extreme mechanical crowding from a broncho constrictive attack causes inflammation by wounding airway epithelium. Whereas most therapies focus on modulating down-stream inflammatory symptoms, our studies suggest that blocking epithelial extrusion could prevent the feed-forward asthma inflammatory cycle.
登录
查看更多内容
冷冻保存后精密切割肺切片的气道收缩力。
DOI：
10.1165/rcmb.2013-0166ma
发表时间：
2014
影响因子：
6.4
作者：
Rosner,SoniaR;Ram-Mohan,Sumati;Paez-Cortez,JesusR;Lavoie,TeraL;Dowell,MariaL;Yuan,Lei;Ai,Xingbin;Fine,Alan;Aird,WilliamC;Solway,Julian;Fredberg,JeffreyJ;Krishnan,Ramaswamy
通讯作者：
Krishnan,Ramaswamy
影响因子：
14.2
作者：
Price, Megan M.;Oskeritzian, Carole A.;Falanga, Yves T.;Harikumar, Kuzhuvelil B.;Allegood, Jeremy C.;Alvarez, Sergio E.;Conrad, Daniel;Ryan, John J.;Milstien, Sheldon;Spiegel, Sarah
通讯作者：
Spiegel, Sarah
正常儿童和哮喘儿童乙酰甲胆碱吸入挑战的特异性和敏感性。
影响因子：
14.2
作者：
Russell J. Hopp;A. Bewtra;N. Nair;Robert G. Townley
通讯作者：
Robert G. Townley
DOI：
10.1164/ajrccm.165.1.2105051
发表时间：
2002-01-01
影响因子：
24.7
作者：
Henderson, WR;Tang, LO;Chi, EY
通讯作者：
Chi, EY
影响因子：
12.4
作者：
Fuerst E;Foster HR;Ward JP;Corrigan CJ;Cousins DJ;Woszczek G
通讯作者：
Woszczek G