Inflammation and coagulation abnormalities via the activation of the HMGB1‑RAGE/NF‑κB and F2/Rho pathways in lung injury induced by acute hypoxia

Gao,Jing; Zhang,Zhuo; Yan,Jia-Yi; Ge,Yun-Xuan; Gao,Yue

doi:10.3892/ijmm.2023.5270

Inflammation and coagulation abnormalities via the activation of the HMGB1‑RAGE/NF‑κB and F2/Rho pathways in lung injury induced by acute hypoxia

Authors:
- Jing Gao
- Zhuo Zhang
- Jia-Yi Yan
- Yun-Xuan Ge
- Yue Gao
View Affiliations

Affiliations: Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
Published online on: June 20, 2023 https://doi.org/10.3892/ijmm.2023.5270
Article Number: 67
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

High‑altitude acute hypoxia is commonly associated with respiratory cardiovascular diseases. The inability to adapt to acute hypoxia may lead to cardiovascular dysfunction, lung injury and even death. Therefore, understanding the molecular basis of the adaptation to high‑altitude acute hypoxia may reveal novel therapeutic approaches with which to counteract the detrimental consequences of hypoxia. In the present study, a high‑altitude environment was simulated in a rat model in order to investigate the role of the high mobility group protein‑1 (HMGB1)/receptor for advanced glycation end products (RAGE)/NF‑κB and F2/Rho signaling pathways in lung injury induced by acute hypoxia. It was found that acute hypoxia caused inflammation through the HMGB1/RAGE/NF‑κB pathway and coagulation dysfunction through the F2/Rho pathway, both of which may be key processes in acute hypoxia‑induced lung injury. The present study provides new insight into the molecular basis of lung injury induced by acute hypoxia. The simultaneous activation of the HMGB1/RAGE/NF‑κB and F2/Rho signaling pathways plays a critical role in hypoxia‑induced inflammatory responses and coagulation abnormalities, and provides a theoretical basis for the development of potential therapeutic strategies.

View Figures

View References

1	Yu SL, Wong CK, Szeto CC, Li EK, Cai Z and Tam LS: Members of the receptor for advanced glycation end products axis as potential therapeutic targets in patients with lupus nephritis. Lupus. 24:675–686. 2015. View Article : Google Scholar
2	Hudson BI and Lippman ME: Targeting RAGE signaling in inflammatory disease. Ann Rev Med. 69:349–364. 2018. View Article : Google Scholar
3	Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR and Kennedy TP: Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol. 299:C97–C110. 2010. View Article : Google Scholar
4	Degani G, Altomare A, Digiovanni S, Arosio B, Fritz G, Raucci A, Aldini G and Popolo L: Prothrombin is a binding partner of the human receptor of advanced glycation end products. J Biol Chem. 295:12498–12511. 2020. View Article : Google Scholar : PubMed/NCBI
5	Zhang C, Dong H, Chen F, Wang Y, Ma J and Wang G: The HMGB1-RAGE/TLR-TNF-α signaling pathway may contribute to kidney injury induced by hypoxia. Exp Ther Med. 17:17–26. 2019.
6	Sokolova E and Reiser G: A novel therapeutic target in various lung diseases: Airway proteases and protease-activated receptors. Pharmacol Ther. 115:70–83. 2007. View Article : Google Scholar : PubMed/NCBI
7	Demling N, Ehrhardt C, Kasper M, Laue M, Knels L and Rieber EP: Promotion of cell adherence and spreading: A novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tissue Res. 323:475–488. 2006. View Article : Google Scholar
8	Lizotte PP, Hanford LE, Enghild JJ, Nozik-Grayck E, Giles BL and Oury TD: Developmental expression of the receptor for advanced glycation end-products (RAGE) and its response to hyperoxia in the neonatal rat lung. BMC Dev Biol. 7:152007. View Article : Google Scholar
9	Gross CM, Kellner M, Wang T, Lu Q, Sun X, Zemskov EA, Noonepalle S, Kangath A, Kumar S, Gonzalez-Garay M, et al: LPS-induced acute lung injury involves NF-κB-mediated downregulation of SOX18. Am J Respir Cell Mol Biol. 58:614–624. 2018. View Article : Google Scholar
10	Johnson ER and Matthay MA: Acute lung injury: Epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 23:243–252. 2010. View Article : Google Scholar : PubMed/NCBI
11	Blank R and Napolitano LM: Epidemiology of ARDS and ALI. Crit Care Clin. 27:439–458. 2011. View Article : Google Scholar : PubMed/NCBI
12	Camprubí-Rimblas M, Tantinyà N, Bringué J, Guillamat-Prats R and Artigas A: Anticoagulant therapy in acute respiratory distress syndrome. Ann Transl Med. 6:362018. View Article : Google Scholar : PubMed/NCBI
13	Geering B, Gurzeler U, Federzoni E, Kaufmann T and Simon HU: A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils. Blood. 117:5953–5962. 2011. View Article : Google Scholar : PubMed/NCBI
14	Itakura E, Huang RR, Wen DR, Paul E, Wünsch PH and Cochran AJ: IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod Pathol. 24:801–809. 2011. View Article : Google Scholar : PubMed/NCBI
15	Gao XJ, Qu YY, Liu XW, Zhu M, Ma CY, Jiao YL, Cui B, Chen ZJ and Zhao YR: Immune complexes induce TNF-α and BAFF production from U937 cells by HMGB1 and RAGE. Eur Rev Med Pharmacol Sci. 21:1810–1819. 2017.PubMed/NCBI
16	Fritz G: RAGE: A single receptor fits multiple ligands. Trends Biochem Sci. 36:625–632. 2011. View Article : Google Scholar
17	Bangert A, Andrassy M, Müller AM, Bockstahler M, Fischer A, Volz CH, Leib C, Göser S, Korkmaz-Icöz S, Zittrich S, et al: Critical role of RAGE and HMGB1 in inflammatory heart disease. Proc Natl Acad Sci USA. 113:E155–E164. 2016. View Article : Google Scholar
18	Scaffidi P, Misteli T and Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418:191–195. 2002. View Article : Google Scholar : PubMed/NCBI
19	Sanders A, Delker DA, Huecksteadt T, Beck E, Wuren T, Chen Y, Zhang Y, Hazel MW and Hoidal JR: RAGE is a critical mediator of pulmonary oxidative stress, alveolar macrophage activation and emphysema in response to cigarette smoke. Sci Rep. 9:2312019. View Article : Google Scholar : PubMed/NCBI
20	Pilzweger C and Holdenrieder S: Circulating HMGB1 and RAGE as clinical biomarkers in malignant and autoimmune diseases. Diagnostics (Basel). 5:219–253. 2015. View Article : Google Scholar
21	Zhang QY, Wu LQ, Zhang T, Han YF and Lin X: Autophagy-mediated HMGB1 release promotes gastric cancer cell survival via RAGE activation of extracellular signal-regulated kinases 1/2. Oncol Rep. 33:1630–1638. 2015. View Article : Google Scholar : PubMed/NCBI
22	Ségal-Bendirdjian E and Geli V: Non-canonical roles of telomerase: Unraveling the imbroglio. Front Cell Dev Biol. 7:3322019. View Article : Google Scholar
23	Ghosh S and Hayden M: New regulators of NF-kappa B in inflammation. Nat Rev Immunol. 8:837–848. 2008. View Article : Google Scholar
24	Shen Y, Xie X, Li Z, Huang Y, Ma L, Shen X, Liu Y and Zhao Y: Interleukin-17-induced expression of monocyte chemoattractant protein-1 in cardiac myocytes requires nuclear factor κB through the phosphorylation of p65. Microbiol Immunol. 61:280–286. 2017. View Article : Google Scholar : PubMed/NCBI
25	Zhu A, Sun H, Raymond RM Jr, Furie BC, Furie B, Bronstein M, Kaufman RJ, Westrick R and Ginsburg D: Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase. Blood. 109:5270–5275. 2007. View Article : Google Scholar : PubMed/NCBI
26	Innerhofer P and Kienast J: Principles of perioperative coagulopathy. Best Pract Res Clin Anaesthesiol. 24:1–14. 2010. View Article : Google Scholar : PubMed/NCBI
27	Terada M, Kelly EA and Jarjour NN: Increased thrombin activity after allergen challenge: A potential link to airway remodeling? Am J Respir Crit Care Med. 169:373–377. 2004. View Article : Google Scholar
28	Bartko J, Schoergenhofer C, Schwameis M, Buchtele N, Wojta J, Schabbauer G, Stiebellehner L and Jilma B: Dexamethasone inhibits endotoxin-induced coagulopathy in human lungs. J Thromb Haemost. 14:2471–2477. 2016. View Article : Google Scholar : PubMed/NCBI
29	Stroo I, Ding C, Novak A, Yang J, Roelofs JJTH, Meijers JCM, Revenko AS, van't Veer C, Zeerleder S, Crosby JR and van der Poll T: Inhibition of the extrinsic or intrinsic coagulation pathway during pneumonia-derived sepsis. Am J Physiol Lung Cell Mol Physiol. 315:L799–L809. 2018. View Article : Google Scholar : PubMed/NCBI
30	Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, Luger TA and Hollenberg MD: Proteinase-activated receptors: Transducers of proteinase-mediated signaling in inflammation and immune response. Endocrine Rev. 26:1–43. 2005. View Article : Google Scholar
31	Bar-Shavit R, Benezra M, Sabbah V, Bode W and Vlodavsky I: Thrombin as a multifunctional protein: Induction of cell adhesion and proliferation. Am J Respir Cell Mol Biol. 6:123–130. 1992. View Article : Google Scholar
32	Ellis CA, Malik AB, Gilchrist A, Hamm H, Sandoval R, Voyno-Yasenetskaya T and Tiruppathi CP: Thrombin induces proteinase-activated receptor-1 gene expression in endothelial cells via activation of Gi-linked Ras/mitogen-activated protein kinase pathway. J Biol Chem. 274:13718–13727. 1999. View Article : Google Scholar : PubMed/NCBI
33	Gopal P, Gosker HR, de Theije CC, Eurlings IM, Sell DR, Monnier VM and Reynaert P: Effect of chronic hypoxia on RAGE and its soluble forms in lungs and plasma of mice. Biochim Biophys Acta. 1852:992–1000. 2015. View Article : Google Scholar : PubMed/NCBI
34	Li Y, Wu R, Zhao S, Cheng H, Ji P, Yu M and Tian Z: RAGE/NF-κB pathway mediates lipopolysaccharide-induced inflammation in alveolar type I epithelial cells isolated from neonate rats. Inflammation. 37:1623–1629. 2014. View Article : Google Scholar : PubMed/NCBI
35	Alexiou P, Chatzopoulou M, Pegklidou K and Demopoulos VJ: A multi-ligand receptor unveiling novel insights in health and disease. Curr Med Chem. 17:2232–2252. 2010. View Article : Google Scholar
36	Feng Y, Ke J, Cao P, Deng M, Li J, Cai H, Meng Q, Li Y and Long X: HMGB1-induced angiogenesis in perforated disc cells of human temporomandibular joint. J Cell Mol Med. 22:1283–1291. 2018.
37	He F, Gu L, Cai N, Ni J, Liu Y, Zhang Q and Wu C: The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress. Inflamm Res. 71:1245–1260. 2022. View Article : Google Scholar
38	Sharma AK, LaPar DJ, Stone ML, Zhao Y, Kron IL and Laubach VE: Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury. Am J Transplant. 13:2255–2267. 2013. View Article : Google Scholar : PubMed/NCBI
39	Mi L, Zhang Y, Xu Y, Zheng X, Zhang X, Wang Z, Xue M and Jin X: HMGB1/RAGE pro-inflammatory axis promotes vascular endothelial cell apoptosis in limb ischemia/reperfusion injury. Biomed Pharmacother. 116:1090052019. View Article : Google Scholar : PubMed/NCBI
40	Andersson U, Yang H and Harris H: High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells. Semin Immunol. 38:40–48. 2018. View Article : Google Scholar : PubMed/NCBI
41	Cuenda A and Rousseau S: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 1773:1358–1375. 2007. View Article : Google Scholar
42	Heinbockel L, Sánchez-Gómez S, de Tejada GM, Dömming S, Brandenburg J, Kaconis Y, Hornef M, Dupont A, Marwitz S, Goldmann T, et al: Preclinical investigations reveal the broad-spectrum neutralizing activity of peptide Pep19-2.5 on bacterial pathogenicity factors. Antimicrob Agents Chemother. 57:1480–1487. 2013. View Article : Google Scholar :
43	Entezari M, Javdan M, Antoine DJ, Morrow DM, Sitapara RA, Patel V, Wang M, Sharma L, Gorasiya S, Zur M, et al: Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury. Redox Biol. 2:314–322. 2014. View Article : Google Scholar : PubMed/NCBI
44	Zhao MJ, Jiang HR, Sun JW, Wang ZA, Hu B, Zhu CR, Yin XH, Chen MM, Ma XC, Zhao WD and Luan ZG: Roles of RAGE/ROCK1 pathway in HMGB1-induced early changes in barrier permeability of human pulmonary microvascular endothelial cell. Front Immunol. 12:6970712021. View Article : Google Scholar : PubMed/NCBI
45	Paudel YN, Angelopoulou E, Piperi C, Balasubramaniam V, Othman I and Shaikh MF: Enlightening the role of high mobility group box 1 (HMGB1) in inflammation: Updates on receptor signalling. Eur J Pharmacol. 858:1724872019. View Article : Google Scholar : PubMed/NCBI
46	Joshi N, Walter JM and Misharin AV: Alveolar macrophages. Cell Immunol. 330:86–90. 2018. View Article : Google Scholar : PubMed/NCBI
47	Gonzalez NC and Wood JG: Alveolar hypoxia-induced systemic inflammation: What low PO(2) does and does not do. Adv Exp Med Biol. 662:27–32. 2010. View Article : Google Scholar : PubMed/NCBI
48	Fröhlich S, Boylan J and McLoughlin P: Hypoxia-induced inflammation in the lung: A potential therapeutic target in acute lung injury? Am J Respir Cell Mol Biol. 48:271–279. 2013. View Article : Google Scholar
49	Minamino T, Christou H, Hsieh CM, Liu Y, Dhawan V, Abraham NG, Perrella MA, Mitsialis SA and Kourembanas S: Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci USA. 98:8798–8803. 2001. View Article : Google Scholar : PubMed/NCBI
50	Vergadi E, Chang MS, Lee C, Liang OD, Liu X, Fernandez-Gonzalez A, Mitsialis SA and Kourembanas S: Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation. 123:1986–1995. 2011. View Article : Google Scholar :
51	Carpenter TC and Stenmark KR: Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak. Am J Physiol. 281:L941–L948. 2001.
52	Wang M and Cheong KL: Preparation, structural characterisation, and bioactivities of fructans: A review. Molecules. 28:16132023. View Article : Google Scholar : PubMed/NCBI
53	Chen GY and Nuñez G: Sterile inflammation: Sensing and reacting to damage. Nat Rev. 10:826–837. 2010.
54	Eltzschig HK and Eckle T: Ischemia and reperfusion-from mechanism to translation. Nat Med. 17:1391–1401. 2011. View Article : Google Scholar
55	Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N and Chilvers ER: Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med. 201:105–115. 2005. View Article : Google Scholar : PubMed/NCBI
56	Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF and Eltzschig HK: A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood. 111:2024–2035. 2008. View Article : Google Scholar
57	Eltzschig HK and Carmeliet P: Hypoxia and inflammation. New Engl J Med. 364:656–665. 2011. View Article : Google Scholar : PubMed/NCBI
58	Zhu S, Li W, Ward MF, Sama AE and Wang H: High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation. Inflamm Allergy Drug Targets. 9:60–72. 2010. View Article : Google Scholar :
59	Smolarczyk R, Cichoń T, Jarosz M and Szala S: HMGB1-its role in tumor progression and anticancer therapy. Postepy Hig Med Dosw (Online). 66:913–920. 2012.In Polish. View Article : Google Scholar
60	Yamada Y, Fujii T, Ishijima R, Tachibana H, Yokoue N, Takasawa R and Tanuma S: The release of high mobility group box 1 in apoptosis is triggered by nucleosomal DNA fragmentation. Arch Biochem Biophys. 506:188–193. 2011. View Article : Google Scholar
61	Zhang Y, Zhang M, Wang CY and Shen A: Ketamine alleviates LPS induced lung injury by inhibiting HMGB1-RAGE level. Eur Rev Med Pharmacol Sci. 22:1830–1836. 2018.PubMed/NCBI
62	Chavakis T, Bierhaus A and Nawroth PP: RAGE (receptor for advanced glycation end products): A central player in the inflammatory response. Microbes Infect. 6:1219–1225. 2004. View Article : Google Scholar : PubMed/NCBI
63	Wang L, Li JY, Zhang XZ, Liu L, Wan ZM, Li RX and Guo Y: Involvement of p38mapk/nf-κb signaling pathways in osteoblasts differentiation in response to mechanical stretch. Ann Biomed Eng. 40:1884–1894. 2012. View Article : Google Scholar : PubMed/NCBI
64	Ott I: Soluble tissue factor emerges from inflammation. Circ Res. 96:1217–1218. 2005. View Article : Google Scholar : PubMed/NCBI
65	Erlich JH, Boyle EM, Labriola J, Kovacich JC, Santucci RA, Fearns C, Morgan EN, Yun W, Luther T, Kojikawa O, et al: Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol. 157:1849–1862. 2000. View Article : Google Scholar : PubMed/NCBI
66	Carr C, Bild GS, Chang AC, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun TC, Creasey AA and Hinshaw LB: Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock. 44:126–137. 1994.PubMed/NCBI
67	Ware LB and Calfee CS: Biomarkers of ARDS: what's new? Intensive Care Med. 42:797–799. 2016. View Article : Google Scholar