Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels.
Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels.
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DOI：
10.3389/fphys.2023.1118770
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发表时间：
2023
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
西格玛1受体蛋白（Sigmar1）是一种小型多功能分子伴侣蛋白，几乎在所有身体组织中普遍表达。此前研究表明，该蛋白在啮齿动物的心肌肥大、心力衰竭及缺血 - 再灌注损伤模型中具有心脏保护作用。大量文献还指出其在多种中枢神经系统疾病中具有保护功能。然而，Sigmar1在肺系统中的分子功能仍不明确。因此，我们旨在确定Sigmar1在肺中的表达情况。我们还研究了在小鼠衰老过程中，敲除Sigmar1是否会导致与肺部病理相关的组织学、超微结构和生化变化。
在本研究中，我们首先通过免疫组织化学和免疫染色证实了Sigmar1蛋白在人和小鼠肺中的存在。我们使用Sigmar1全身敲除小鼠（Sigmar1−/−）来确定Sigmar1在小鼠衰老过程中对肺的病理生理作用。肺组织切片的组织学染色显示，与野生型（Wt）同窝对照小鼠相比，Sigmar1−/−小鼠的肺泡结构改变、免疫细胞浸润增多，且炎症标志物（如pNFκB）上调。这表明小鼠中Sigmar1缺乏会导致肺部炎症加剧，并与肺纤维化增加有关。与野生型小鼠相比，在缺乏Sigmar1的小鼠肺中，一些纤维化标志物（纤连蛋白、pSMAD2 Ser 245/250/255和Ser 465/467）的蛋白水平也有所升高。
对野生型小鼠肺的超微结构分析显示，存在大量不同大小的多层体，其脂质片层紧密堆积，线粒体基质深染且嵴密集。相比之下，Sigmar1−/−小鼠肺组织中，肺泡II型上皮细胞内的多层体结构发生改变，层状体中的脂质片层结构部分缺失。这进一步与Sigmar1−/−小鼠肺中所有四种表面活性蛋白（SFTP - A、SFTP - B、SFTP - C和SFTP - D）的蛋白水平升高有关。
这是首次研究Sigmar1在人和小鼠肺中的表达模式及其与肺病理生理学的关联。我们的研究结果表明，Sigmar1缺乏会导致肺部炎症增加、肺纤维化加重、多层体结构改变以及肺表面活性蛋白水平升高。
Sigma1 receptor protein (Sigmar1) is a small, multifunctional molecular chaperone protein ubiquitously expressed in almost all body tissues. This protein has previously shown its cardioprotective roles in rodent models of cardiac hypertrophy, heart failure, and ischemia-reperfusion injury. Extensive literature also suggested its protective functions in several central nervous system disorders. Sigmar1’s molecular functions in the pulmonary system remained unknown. Therefore, we aimed to determine the expression of Sigmar1 in the lungs. We also examined whether Sigmar1 ablation results in histological, ultrastructural, and biochemical changes associated with lung pathology over aging in mice. In the current study, we first confirmed the presence of Sigmar1 protein in human and mouse lungs using immunohistochemistry and immunostaining. We used the Sigmar1 global knockout mouse (Sigmar1−/−) to determine the pathophysiological role of Sigmar1 in lungs over aging. The histological staining of lung sections showed altered alveolar structures, higher immune cells infiltration, and upregulation of inflammatory markers (such as pNFκB) in Sigmar1−/− mice compared to wildtype (Wt) littermate control mice (Wt). This indicates higher pulmonary inflammation resulting from Sigmar1 deficiency in mice, which was associated with increased pulmonary fibrosis. The protein levels of some fibrotic markers, fibronectin, and pSMAD2 Ser 245/250/255 and Ser 465/467, were also elevated in mice lungs in the absence of Sigmar1 compared to Wt. The ultrastructural analysis of lungs in Wt mice showed numerous multilamellar bodies of different sizes with densely packed lipid lamellae and mitochondria with a dark matrix and dense cristae. In contrast, the Sigmar1−/− mice lung tissues showed altered multilamellar body structures in alveolar epithelial type-II pneumocytes with partial loss of lipid lamellae structures in the lamellar bodies. This was further associated with higher protein levels of all four surfactant proteins, SFTP-A, SFTP-B, SFTP-C, and SFTP-D, in the Sigmar1−/− mice lungs. This is the first study showing Sigmar1’s expression pattern in human and mouse lungs and its association with lung pathophysiology. Our findings suggest that Sigmar1 deficiency leads to increased pulmonary inflammation, higher pulmonary fibrosis, alterations of the multilamellar body stuructures, and elevated levels of lung surfactant proteins.
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影响因子：
6
作者：
Christian F;Smith EL;Carmody RJ
通讯作者：
Carmody RJ
DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
影响因子：
5.8
作者：
Bhuiyan, Md. Shenuarin;Fukunaga, Kohji
通讯作者：
Fukunaga, Kohji
DOI：
10.1073/pnas.84.4.1010
发表时间：
1987-02-01
影响因子：
11.1
作者：
DOBBS, LG;WRIGHT, JR;NELLENBOGEN, J
通讯作者：
NELLENBOGEN, J
影响因子：
4
作者：
Aishwarya R;Abdullah CS;Morshed M;Remex NS;Bhuiyan MS
通讯作者：
Bhuiyan MS