Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels
Open Access
- 27 March 2023
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Physiology
- Vol. 14, 1118770
- https://doi.org/10.3389/fphys.2023.1118770
Abstract
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 structures, and elevated levels of lung surfactant proteins.This publication has 76 references indexed in Scilit:
- σ1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in miceAmerican Journal of Physiology-Heart and Circulatory Physiology, 2010
- Role of Smad2/3 and p38 MAP kinase in TGF‐β1‐induced epithelial–mesenchymal transition of pulmonary epithelial cellsJournal of Cellular Physiology, 2010
- Dehydroepiandrosterone-Mediated Stimulation of Sigma-1 Receptor Activates Akt-eNOS Signaling in the Thoracic Aorta of Ovariectomized Rats with Abdominal Aortic BandingCardiovascular Therapeutics, 2010
- Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized ratsEmerging Therapeutic Targets, 2009
- Binding of [35S]GTPγS stimulated by (+)-pentazocine, sigma receptor agonist, is abundant in the guinea pig spleenLife Sciences, 2000
- Cloning and Structural Analysis of the cDNA and the Gene Encoding the Murine Type 1 Sigma ReceptorBiochemical and Biophysical Research Communications, 1997
- Cloning and Functional Expression of the Human Type 1 Sigma Receptor (hSigmaR1)Biochemical and Biophysical Research Communications, 1996
- Surfactant apoprotein-A concentration in airway secretions for the detection of pulmonary oedemaEuropean Respiratory Journal, 1996
- Lipid Analysis and Surfactant-Associated Protein Expression in Lung Adenocarcinoma Cells from Pleural EffusionRespiration, 1996
- Lamellar bodies of cultured human fetal lung: Content of surfactant protein A (SP-A), surface film formation and structural transformation in vitroBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1990