Oxidative stress and expression of inflammatory factors in lung tissue of acute mountain sickness rats

Pu,Xiaoyan; Li,Fuxin; Lin,Xue; Wang,Rong; Chen,Zhi

doi:10.3892/mmr.2021.12565

Oxidative stress and expression of inflammatory factors in lung tissue of acute mountain sickness rats

Authors:
- Xiaoyan Pu
- Fuxin Li
- Xue Lin
- Rong Wang
- Zhi Chen
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Affiliations: Qinghai Normal University, Xining, Qinghai 810001, P.R. China, College of Medicine, Qinghai University, Xining, Qinghai 810001, P.R. China
Published online on: December 9, 2021 https://doi.org/10.3892/mmr.2021.12565
Article Number: 49
Copyright: © Pu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the changes in lung histomorphology and oxidative stress, as well as the expression of interleukin (IL)‑17C and other inflammatory factors during acute mountain sickness (AMS) in male Sprague‑Dawley rats and to explore the underlying mechanism. Rats were randomly divided into a control group (0 h) and three hypoxia stress groups, exposed to low‑pressure oxygen storage at a simulated altitude of 6,000 m for 24, 48 and 72 h, respectively. Morphological changes in lung tissue were observed by hematoxylin and eosin staining under light microscopy and transmission electron microscopy. The expression of inflammatory factors IL‑17C, nuclear factor‑κB (NF‑κB), IL‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α) in lung tissue was assessed by RNA sequencing and verified by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting (WB). Superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) enzyme activity and malondialdehyde (MDA) expression were also measured. Experimental groups were compared to the control group following 24, 48 and 72 h of hypoxic stress. Lung tissue suffered from different degrees of injury, and the damage was the most severe after 48 h of hypoxic stress. RNA sequencing data from the lung tissue of rats from each group suggested that the expression of IL‑17C, NF‑κB, IL‑1β, IL‑6, and TNF‑α increased significantly after hypoxic stress. RT‑qPCR and WB demonstrated that the expression of IL‑17C and NF‑κB increased significantly after hypoxia lasting 48 and 72 h. IL‑1β expression increased significantly after hypoxia stress lasting 24 and 48 h, and the expressions of TNF‑α and IL‑6 increased significantly after hypoxia stress lasting 24, 48 and 72 h (P<0.01). The enzyme activity of SOD and GSH‑Px decreased significantly after lasting 24, 48 and 72 h of hypoxia (P<0.01), and MDA increased significantly after hypoxic stress lasting 48 and 72 h (P<0.01). In conclusion, under hypoxic stress, rats quickly initiate oxidative stress and immune responses. However, with prolonged hypoxic stress time, excessive oxidative stress can further stimulate the immune system in vivo, and release a large quantity of inflammatory factors accumulating in the body. This, in turn, may lead to the occurrence of inflammatory storms and further damage the lung tissue resulting in AMS.

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1	Tang E, Chen Y and Luo Y: Dexamethasone for the prevention of acute mountain sickness: Systematic review and meta-analysis. Int J Cardiol. 173:133–138. 2014. View Article : Google Scholar : PubMed/NCBI
2	Guo P, Luo H, Fan Y, Luo Y and Zhou Q: Establishment and evaluation of an experimental animal model of high altitude cerebral edema. Neurosci Lett. 547:82–86. 2013. View Article : Google Scholar : PubMed/NCBI
3	Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbäurl H and Bärtsch P: Pathogenesis of high-altitude pulmonary edema: Inflammation is not an etiologic factor. JAMA. 287:2228–2235. 2002. View Article : Google Scholar : PubMed/NCBI
4	Zhao S, Zhang L, Lian G, Wang X, Zhang H, Yao X, Yang J and Wu C: Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia. Int Immunopharmacol. 11:468–474. 2011. View Article : Google Scholar : PubMed/NCBI
5	Wyse C, Cathcart A, Sutherland R, Ward S, McMillan L, Gibson G, Padgett M and Skeldon K: Effect of maximal dynamic exercise on exhaled ethane and carbon monoxide levels in human, equine, and canine athletes. Comp Biochem Physiol A Mol Integr Physiol. 141:239–246. 2005. View Article : Google Scholar : PubMed/NCBI
6	Balan DJ, Rajavel T, Das M, Sathya S, Jeyakumar M and Devi KP: Thymol induces mitochondrial pathway-mediated apoptosis via ROS generation, macromolecular damage and SOD diminution in A549 cells. Pharmacol Rep. 73:240–254. 2021. View Article : Google Scholar : PubMed/NCBI
7	Ma Y, Wang D, Xu X, Yang X, Wang X, Zhu Z, Zhao Y, Chen M, Xu F, Fu L, et al: Dynamic changes of ROS, MDA and SOD during arsenic-induced neoplastic transformation in human keratinocytes. Wei Sheng Yan Jiu. 44:456–461. 2015.(In Chinese). PubMed/NCBI
8	Zi Y, Jiang B, He C and Liu L: Lentinan inhibits oxidative stress and inflammatory cytokine production induced by benzo(a)pyrene in human keratinocytes. J Cosmet Dermatol. 19:502–507. 2020. View Article : Google Scholar : PubMed/NCBI
9	Altamura S, Bärtsch P, Dehnert C, Maggiorini M, Weiss G, Theurl I, Muckenthaler MU and Mairbäurl H: Increased hepcidin levels in high-altitude pulmonary edema. J Appl Physiol (1985). 118:292–298. 2015. View Article : Google Scholar : PubMed/NCBI
10	Gao H, Liu L, Zhao Y, Hara H, Chen P, Xu J, Tang J, Wei L, Li Z, Cooper DK, et al: Human IL-6, IL-17, IL-1β, and TNF-α differently regulate the expression of pro-inflammatory related genes, tissue factor, and swine leukocyte antigen class I in porcine aortic endothelial cells. Xenotransplantation. 24:2017. View Article : Google Scholar
11	Sun Y, Hu G, Zhang X and Minshall RD: Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellularand transcellular pathways. Circ Res. 105:676–685. 2009. View Article : Google Scholar : PubMed/NCBI
12	Shukla D, Saxena S, Jayamurthy P, Sairam M, Singh M, Jain SK, Bansal A and Ilavazaghan G: Hypoxic preconditioning with cobalt attenuates hypobaric hypoxia-induced oxidative damage inratlungs. High Alt Med Biol. 10:57–69. 2009. View Article : Google Scholar : PubMed/NCBI
13	Gonzalez NC and Wood JG: Leukocyte endothelial interactions in environmental hypoxia. Adv Exp Med Biol. 502:39–60. 2001. View Article : Google Scholar : PubMed/NCBI
14	Xiao-Lin MA, Jin RB, Zhang XH, Cui GY, Ren XJ, Shi H and Sun YQ: Study on management of 726 victims in military hospitals following Yushu earthquake in Qinghai province. J Traumat Surg. 4:339–343. 2010.(In Chinese).
15	Tang C, Luo Y, Li S, Huang B, Xu S and Li L: Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats. Biomed Pharmacother. 133:1110812021. View Article : Google Scholar : PubMed/NCBI
16	Han Z, Li X, Cui X, Yuan H and Wang H: The roles of immune system and autoimmunity in pulmonary arterial hypertension: A review. Pulm Pharmacol Ther 102094. Nov 2–2021.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
17	Hu DL, Yu YX, Liang R, Zhou SY, Duan SL, Jiang ZY, Meng CY, Jiang W, Wang H, Sun YX and Fang LS: Regulation of hypoxia inducible factor-1α on permeability of vascular endothelial cells and the mechanism. Zhonghua Shao Shang Za Zhi. 35:209–217. 2019.(In Chinese). PubMed/NCBI
18	Zhou Q, Luo Y, Li H, Li S, Zhang X, Gao W, Zheng B, Yang D, Liu F and Yuqi G: Epidemiological study of mountain sickness complicated with multiple organ dysfunction syndrome on the Qinghai-Tibetan Plateau: report of 103 cases. Sci Res Essays. 5:2010.
19	Althubiti M, Rada M, Samuel J, Escorsa JM, Najeeb H, Lee KG, Lam KP, Jones GD, Barlev NA and Macip S: BTK modulates p53 activity to enhance apoptotic and senescent responses. Cancer Res. 76:5405–5414. 2016. View Article : Google Scholar : PubMed/NCBI
20	Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M, Ciuffetta A, Colantoni S, Vacca A, Frati L, et al: Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. J Immunol. 186:6199–6206. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li H, Chen J, Huang A, Stinson J, Heldens S, Foster J, Dowd P, Gurney AL and Wood WI: Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci USA. 97:773–778. 2000. View Article : Google Scholar : PubMed/NCBI
22	Song X, He X, Li X and Qian Y: The roles and functional mechanisms ofinterleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol. 13:418–431. 2016. View Article : Google Scholar : PubMed/NCBI
23	Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD and Qian Y: IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. NatImmunol. 12:1151–1158. 2011.
24	Akitsu A and Iwakura Y: Interleukin-17-producing γδ T (γδ17) cells in inflammatory diseases. Immunology. 155:418–426. 2018. View Article : Google Scholar : PubMed/NCBI
25	Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Tsuno NH, Takahashi K and Yamamoto K: IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol. 179:7128–7136. 2007. View Article : Google Scholar : PubMed/NCBI
26	Ruiz de Morales JMG, Puig L, Daudén E, Cañete JD, Pablos JL, Martín AO, Juanatey CG, Adán A, Montalbán X, Borruel N, et al: Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies. Autoimmun Rev. 19:1024292020. View Article : Google Scholar : PubMed/NCBI
27	Yu S, Luo X, Yang B, Xiao L, Wu X, Li H and Wu C: Poly-functional T helper cells in human tonsillar mononuclear cells. Eur Cytokine Netw. 30:114–122. 2019.PubMed/NCBI
28	De-Doncker L, Picquet F, Petit J and Falempin M: Characterization of spindle afferents in rat soleus muscle using ramp-and-hold and sinusoidal stretches. J Neurophysiol. 89:442–449. 2003. View Article : Google Scholar : PubMed/NCBI
29	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
30	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
31	Ryan CF, Lowe AA and Fleetham JA: Nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea in Hallermann-Streiff syndrome. Clin Pediatr (Phila). 29:122–124. 1990. View Article : Google Scholar : PubMed/NCBI
32	Maggiorini M, Mélot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U and Naeije R: High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation. 103:2078–2083. 2001. View Article : Google Scholar : PubMed/NCBI
33	Luo X, Guo W, Xu R, et al: Effect of high altitude and hypoxia in simulated environment on HPT axis and expression of VEGF and HIF-1 in lung tissues of rats. Acad J Chin PLA Med Sch. 37:864–868. 2016.(In Chinese).
34	Guo W: The dynamic observation of hypothalamic-pituitary-adrenala axis/hypothalamic-pituitary-thyroid axis stress and the effect of lung and brain tissue under simulated high altitude hypoxia. Gan Su University of Chinese Medicine; 2016, (In Chinese).
35	Li Y: The research of hypoxia related genes in high altitude pulmonary edema. Qing Hai University; 2017, (In Chinese).
36	Brandon M, Baldi P and Wallace DC: Mitochondrial mutations in cancer. Oncogene. 25:4647–4662. 2006. View Article : Google Scholar : PubMed/NCBI
37	Morrow JD: Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler Thromb Vasc Biol. 25:279–286. 2005. View Article : Google Scholar : PubMed/NCBI
38	Zhou L, Aon MA, Almas T, Cortassa S, Winslow RL and O'Rourke B: A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network. PLoS Comput Biol. 6:e10006572010. View Article : Google Scholar : PubMed/NCBI
39	Xiong R, Jiang W, Li N, Liu B, He R, Wang B and Geng Q: PM2.5-induced lung injury is attenuated in macrophage-specific NLRP3 deficient mice. Ecotoxicol Environ Saf. 221:1124332021. View Article : Google Scholar : PubMed/NCBI
40	Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, Hackney J, Kim J, Zhou M, Lai J, et al: IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol. 12:1159–1166. 2011. View Article : Google Scholar : PubMed/NCBI
41	Uberti F, Lattuada D, Morsanuto V, Nava U, Bolis G, Vacca G, Squarzanti DF, Cisari C and Molinari C: Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways. J Clin Endocrinol Metab. 99:1367–1374. 2014. View Article : Google Scholar : PubMed/NCBI