Correlation between osteoprotegerin / receptor activator of nuclear factor-κB ligand ratio and sepsis-related acute lung injury_West China Medical Journal

Authors：

CHEN Weilin ¹ , MAIMAITI Yisireyili ² , LI Hui ¹ ,  NIU Xinrong ³

1. Graduate School, Xinjiang Medical University, Urumqi, Xinjiang 830017, P. R. China;
2. Research and Education Center, Xinjiang Uygur Autonomous Region People’s Hospital, Urumqi, Xinjiang 830001, P. R. China;
3. Second Department of Intensive Care Medicine, Xinjiang Uygur Autonomous Region People’s Hospital, Urumqi, Xinjiang 830001, P. R. China;

Corresponding author：

NIU Xinrong, Email: 1361498549@qq.com

Keywords：

Sepsis; acute lung injury; osteoprotegerin; receptor activator of nuclear factor-κb ligand; mouse

DOI：

10.7507/1002-0179.202411225

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Objective To investigate the changes in osteoprotegerin (OPG) / receptor activator of nuclear factor-κB ligand (RANKL) ratio in sepsis-associated acute lung injury (SA-ALI) and the role of regulation of this ratio on the inflammatory response in SA-ALI. Methods Eighteen C57BL/6 male mice were randomly divided into sham operation group, cecal ligation and perforation (CLP) group and RANKL group, with 6 mice in each group. Before the experiment, the RANKL group was intraperitoneally injected with 5 μg (0.2 mL) of recombinant RANKL antibody, whereas both the sham operation group and the CLP group were intraperitoneally injected with a volume-matched normal saline. One hour later, the sham operation group underwent only abdominal exploration and repositioning, while the other groups underwent the CLP surgery to induce the SA-ALI model. After 24 h of modelling, all mice were sacrificed and samples were collected. Pathological evaluation of lung tissues was performed by haematoxylin-eosin staining; enzyme-linked immunosorbent assay was used to detect serum concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β; while the mRNA and protein expression of OPG and RANKL, along with their ratio values, were detected by real-time polymerase chain reaction for quantitative analysis and protein immunoblotting. Results The SA-ALI mouse model was successfully established. Compared with the sham operation group, mice in the CLP group showed disturbed alveolar structure, obvious alveolar and interstitial haemorrhage and inflammatory cell infiltration, elevated serum levels of IL-6, TNF-α and IL-1β (P<0.05), significantly increased mRNA and protein expression of OPG and elevated OPG/RANKL ratio in lung tissue (P<0.05), whereas RANKL mRNA and protein expression was significantly decreased (P<0.05). Compared with the CLP group, the pathological damage of lung tissue in the RANKL group was reduced, the infiltration of alveolar and interstitial inflammatory cells was significantly improved, and the alveolar structure and morphology were more regular, with lower serum levels of IL-6, TNF-α and IL-1β (P<0.05), significantly lower mRNA and protein expression of OPG and OPG/RANKL ratio in lung tissue (P<0.05), and significantly higher mRNA and protein expression of RANKL in lung tissue (P<0.05). Conclusion The alteration of OPG/RANKL ratio may be related to the pathophysiological process of SA-ALI, and the decrease in its level may reflect the attenuation of the inflammatory response in SA-ALI.

Citation： CHEN Weilin, MAIMAITI Yisireyili, LI Hui, NIU Xinrong. Correlation between osteoprotegerin / receptor activator of nuclear factor-κB ligand ratio and sepsis-related acute lung injury. West China Medical Journal, 2025, 40(8): 1242-1248. doi: 10.7507/1002-0179.202411225 Copy

1.	Cajander S, Kox M, Scicluna BP, et al. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. Lancet Respir Med, 2024, 12(4): 305-322.
2.	Sun B, Lei M, Zhang J, et al. Acute lung injury caused by sepsis: how does it happen?. Front Med (Lausanne), 2023, 10: 1289194.
3.	Fan SY, Zhao ZC, Liu XL, et al. Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1β signaling pathway. J Inflamm Res, 2024, 17: 3785-3799.
4.	Gong T, Zhang X, Liu X, et al. Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury. Transl Res, 2024, 270: 66-80.
5.	Zhu Z, Chambers S, Bhatia M. Suppressing the substance P-NK1R signalling protects mice against sepsis-associated acute inflammatory injury and ferroptosis in the liver and lungs. Antioxidants (Basel), 2024, 13(3): 300.
6.	Wang K, Kou Y, Rong X, et al. ED-71 improves bone mass in ovariectomized rats by inhibiting osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis. Drug Des Devel Ther, 2024, 18: 1515-1528.
7.	Yu T, Liu X, Jiang M, et al. Cucumber seed polypeptides regulate RANKL-induced osteoclastogenesis through OPG/RANKL/RANK and NF-κB. In Vitro Cell Dev Biol Anim, 2024, 60(1): 54-66.
8.	Chen M, Hu X, Wu M, et al. Serum levels of OPG, RANKL, and RANKL/OPG ratio in patients with ankylosing spondylitis: a systematic review and meta-analysis. Immunol Invest, 2019, 48(5): 490-504.
9.	Nazar N, Mehmood MH, Siddique R, et al. Assessment of antiarthritic potential of Asparagus dumosus using formaldehyde and CFA-induced arthritic models in rats via modulation of oxidative stress biomarkers and mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2. Inflammopharmacology, 2024, 32(1): 825-847.
10.	Freeman C, A S MD, A S P. Unraveling the intricacies of OPG/RANKL/RANK biology and its implications in neurological disorders-a comprehensive literature review. Mol Neurobiol, 2024, 61(12): 10656-10670.
11.	Celebi Torabfam G, Porsuk MH. The role of the receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio in vascular diseases: a therapeutic approach. Angiology, 2025, 76(4): 309-322.
12.	Zhao S, Fu Y, Li Y, et al. A mechanistic study on the toluidine blue/ photodynamic therapy inhibition of lipopolysaccharide-induced inflammatory response in rat gingival fibroblasts. Lasers Med Sci, 2024, 39(1): 187.
13.	Zhang J, Zheng Y, Wang Y, et al. YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis. Front Immunol, 2022, 13: 884362.
14.	Xu J, Tao L, Jiang L, et al. Moderate hypothermia alleviates sepsis-associated acute lung injury by suppressing ferroptosis induced by excessive inflammation and oxidative stress via the Keap1/GSK3β/Nrf2/GPX4 signaling pathway. J Inflamm Res, 2024, 17: 7687-7704.
15.	Zhu H, Shen F, Liao T, et al. Sporidiobolus pararoseus polysaccharides relieve rheumatoid arthritis by regulating arachidonic acid metabolism and bone remodeling signaling pathway. Int J Biol Macromol, 2024, 281(Pt 1): 136272.
16.	Abdel-Rafei MK, Thabet NM, Amin MM. Concerted regulation of OPG/RANKL/NF-κB/MMP-13 trajectories contribute to ameliorative capability of prodigiosin and/or low dose γ-radiation against adjuvant- induced arthritis in rats. Int Immunopharmacol, 2022, 111: 109068.
17.	Kemperman H, Schrijver IT, Roest M, et al. Osteoprotegerin is higher in sepsis than in noninfectious SIRS and predicts 30-day mortality of SIRS patients in the intensive care. J Appl Lab Med, 2019, 3(4): 559-568.
18.	汤盟, 崔占琴, 王阳阳, 等. 低能量激光对人牙周膜细胞白细胞介素-6、肿瘤坏死因子-α、骨保护素、核因子-κB 受体活化因子配体表达的影响. 华西口腔医学杂志, 2023, 41(5): 521-532.
19.	Rochette L, Meloux A, Rigal E, et al. The role of osteoprotegerin in the crosstalk between vessels and bone: its potential utility as a marker of cardiometabolic diseases. Pharmacol Ther, 2018, 182: 115-132.
20.	Maruyama K, Takada Y, Ray N, et al. Receptor activator of NF-kappa B ligand and osteoprotegerin regulate proinflammatory cytokine production in mice. J Immunol, 2006, 177(6): 3799-3805.
21.	Brinjikji W, Kallmes DF, Virmani R, et al. Endotheliitis and cytokine storm as a mechanism of clot formation in COVID-19 ischemic stroke patients: a histopathologic study of retrieved clots. Interv Neuroradiol, 2023, 28: 15910199231185804.
22.	Cao Y, Cui C, Zhao H, et al. Plasma osteoprotegerin correlates with stroke severity and the occurrence of microembolic signals in patients with acute ischemic stroke. Dis Markers, 2019, 2019: 3090364.
23.	Kichev A, Eede P, Gressens P, et al. Implicating receptor activator of NF-κB (RANK)/RANK ligand signalling in microglial responses to Toll-like receptor stimuli. Dev Neurosci, 2017, 39(1/2/3/4): 192-206.
24.	Corallini F, Celeghini C, Rimondi E, et al. Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells. J Cell Physiol, 2011, 226(9): 2279-2286.
25.	Mota RF, Cavalcanti de Araújo PH, Cezine MER, et al. RANKL impairs the TLR4 pathway by increasing TRAF6 and RANK interaction in macrophages. Biomed Res Int, 2022, 2022: 7740079.

1. Cajander S, Kox M, Scicluna BP, et al. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. Lancet Respir Med, 2024, 12(4): 305-322.
2. Sun B, Lei M, Zhang J, et al. Acute lung injury caused by sepsis: how does it happen?. Front Med (Lausanne), 2023, 10: 1289194.
3. Fan SY, Zhao ZC, Liu XL, et al. Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1β signaling pathway. J Inflamm Res, 2024, 17: 3785-3799.
4. Gong T, Zhang X, Liu X, et al. Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury. Transl Res, 2024, 270: 66-80.
5. Zhu Z, Chambers S, Bhatia M. Suppressing the substance P-NK1R signalling protects mice against sepsis-associated acute inflammatory injury and ferroptosis in the liver and lungs. Antioxidants (Basel), 2024, 13(3): 300.
6. Wang K, Kou Y, Rong X, et al. ED-71 improves bone mass in ovariectomized rats by inhibiting osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis. Drug Des Devel Ther, 2024, 18: 1515-1528.
7. Yu T, Liu X, Jiang M, et al. Cucumber seed polypeptides regulate RANKL-induced osteoclastogenesis through OPG/RANKL/RANK and NF-κB. In Vitro Cell Dev Biol Anim, 2024, 60(1): 54-66.
8. Chen M, Hu X, Wu M, et al. Serum levels of OPG, RANKL, and RANKL/OPG ratio in patients with ankylosing spondylitis: a systematic review and meta-analysis. Immunol Invest, 2019, 48(5): 490-504.
9. Nazar N, Mehmood MH, Siddique R, et al. Assessment of antiarthritic potential of Asparagus dumosus using formaldehyde and CFA-induced arthritic models in rats via modulation of oxidative stress biomarkers and mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2. Inflammopharmacology, 2024, 32(1): 825-847.
10. Freeman C, A S MD, A S P. Unraveling the intricacies of OPG/RANKL/RANK biology and its implications in neurological disorders-a comprehensive literature review. Mol Neurobiol, 2024, 61(12): 10656-10670.
11. Celebi Torabfam G, Porsuk MH. The role of the receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio in vascular diseases: a therapeutic approach. Angiology, 2025, 76(4): 309-322.
12. Zhao S, Fu Y, Li Y, et al. A mechanistic study on the toluidine blue/ photodynamic therapy inhibition of lipopolysaccharide-induced inflammatory response in rat gingival fibroblasts. Lasers Med Sci, 2024, 39(1): 187.
13. Zhang J, Zheng Y, Wang Y, et al. YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis. Front Immunol, 2022, 13: 884362.
14. Xu J, Tao L, Jiang L, et al. Moderate hypothermia alleviates sepsis-associated acute lung injury by suppressing ferroptosis induced by excessive inflammation and oxidative stress via the Keap1/GSK3β/Nrf2/GPX4 signaling pathway. J Inflamm Res, 2024, 17: 7687-7704.
15. Zhu H, Shen F, Liao T, et al. Sporidiobolus pararoseus polysaccharides relieve rheumatoid arthritis by regulating arachidonic acid metabolism and bone remodeling signaling pathway. Int J Biol Macromol, 2024, 281(Pt 1): 136272.
16. Abdel-Rafei MK, Thabet NM, Amin MM. Concerted regulation of OPG/RANKL/NF-κB/MMP-13 trajectories contribute to ameliorative capability of prodigiosin and/or low dose γ-radiation against adjuvant- induced arthritis in rats. Int Immunopharmacol, 2022, 111: 109068.
17. Kemperman H, Schrijver IT, Roest M, et al. Osteoprotegerin is higher in sepsis than in noninfectious SIRS and predicts 30-day mortality of SIRS patients in the intensive care. J Appl Lab Med, 2019, 3(4): 559-568.
18. 汤盟, 崔占琴, 王阳阳, 等. 低能量激光对人牙周膜细胞白细胞介素-6、肿瘤坏死因子-α、骨保护素、核因子-κB 受体活化因子配体表达的影响. 华西口腔医学杂志, 2023, 41(5): 521-532.
19. Rochette L, Meloux A, Rigal E, et al. The role of osteoprotegerin in the crosstalk between vessels and bone: its potential utility as a marker of cardiometabolic diseases. Pharmacol Ther, 2018, 182: 115-132.
20. Maruyama K, Takada Y, Ray N, et al. Receptor activator of NF-kappa B ligand and osteoprotegerin regulate proinflammatory cytokine production in mice. J Immunol, 2006, 177(6): 3799-3805.
21. Brinjikji W, Kallmes DF, Virmani R, et al. Endotheliitis and cytokine storm as a mechanism of clot formation in COVID-19 ischemic stroke patients: a histopathologic study of retrieved clots. Interv Neuroradiol, 2023, 28: 15910199231185804.
22. Cao Y, Cui C, Zhao H, et al. Plasma osteoprotegerin correlates with stroke severity and the occurrence of microembolic signals in patients with acute ischemic stroke. Dis Markers, 2019, 2019: 3090364.
23. Kichev A, Eede P, Gressens P, et al. Implicating receptor activator of NF-κB (RANK)/RANK ligand signalling in microglial responses to Toll-like receptor stimuli. Dev Neurosci, 2017, 39(1/2/3/4): 192-206.
24. Corallini F, Celeghini C, Rimondi E, et al. Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells. J Cell Physiol, 2011, 226(9): 2279-2286.
25. Mota RF, Cavalcanti de Araújo PH, Cezine MER, et al. RANKL impairs the TLR4 pathway by increasing TRAF6 and RANK interaction in macrophages. Biomed Res Int, 2022, 2022: 7740079.

West China Medical Journal

Correlation between osteoprotegerin / receptor activator of nuclear factor-κB ligand ratio and sepsis-related acute lung injury

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