Abstract
Glutaredoxins (Grx) are redox enzymes that remove glutathione bound to protein thiols, know as S-glutathionylation (PSSG). PSSG is a reservoir of GSH and can affect the function of proteins. It inhibits the NF-κB pathway and LPS aspiration in Grx1 KO mice with decreased inflammatory cytokine levels. In this study we investigated whether absence of Grx1 similarly repressed cigarette smoke-induced inflammation in an exposure model in mice. Cigarette smoke exposure for four weeks decreased lung PSSG levels, but increased PSSG in lavaged cells and lavage fluid (BALF). Grx1 KO mice had increased levels of PSSG in lung tissue, BALF and BAL cells in response to smoke compared to wt mice. Importantly, levels of multiple inflammatory mediators in the BALF were decreased in Grx1 KO animals following cigarette smoke exposure compared to wt mice, as were levels of neutrophils, dendritic cells and lymphocytes. On the other hand, macrophage numbers were higher in Grx1 KO mice in response to smoke. Although cigarette smoke in vivo caused inverse effects in inflammatory and resident cells with respect to PSSG, primary macrophages and epithelial cells cultured from Grx1 KO mice both produced less KC compared to cells isolated from WT mice after smoke extract exposure. In this manuscript, we provide evidence that Grx1 has an important role in regulating cigarette smoke-induced lung inflammation which seems to diverge from its effects on total PSSG. Secondly, these data expose the differential effect of cigarette smoke on PSSG in inflammatory versus resident lung cells.
Highlights
The lung continuously encounters oxidants from inhalation and is well equipped with a high concentration of the antioxidant glutathione (GSH)
The total number of BALF cells was found to be significantly elevated in wild type and Grx1 KO mice due to cigarette smoke compared to respective air exposed controls
There was no difference in the total amount of Bronchoalveolar Lavage (BAL) fluid and lung cells between wild type and Grx1 KO mice after smoke exposure, the pattern of inflammatory cells found in the BAL fluid was different
Summary
The lung continuously encounters oxidants from inhalation and is well equipped with a high concentration of the antioxidant glutathione (GSH). Glutathione can in conditions of mild oxidative stress, bind to cysteine residues in proteins. This posttranslational modification is known as S-glutathionylation and protects proteins from irreversible oxidations. Glutaredoxins (Grx) or thioltransferases are redox enzymes that, under physiological conditions, can reverse S-glutathionylation. S-glutathionylation does protect the targeted protein thiol groups from further irreversible oxidations, and has been shown to modulate protein function when the targeted cysteine residue is critical to its function [4]. Glutaredoxins play an important role in redox-modulated protein function by regulating S-glutathionylation. Grx localizes primarily to the cytosol and Grx is present in the mitochondria and nucleus [8]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.