{"title":"The injury effect of osteopontin in sepsis-associated lung injury.","authors":"Qian Wang, Zhicai Yu, Zhixin Song, Xue Lu, Zhu Li, Dandan Pi, Jing Li, Feng Xu","doi":"10.1186/s12950-025-00430-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a severe condition causing organ failure due to an abnormal immune reaction to infection, characterized by ongoing excessive inflammation and immune system issues. Osteopontin (OPN) is secreted by various cells and plays a crucial role in inflammatory responses and immune regulation. Nonetheless, the precise function of OPN in sepsis remains to be elucidated.</p><p><strong>Methods: </strong>In the present study, we evaluated the levels of OPN in paediatric patients with sepsis and healthy individuals. We examined the impact of OPN on survival rates, systemic inflammation, and lung injury within an experimental sepsis model using cecal ligation and puncture (CLP). Furthermore, the pro-inflammatory effects and potential mechanisms of OPN in sepsis were investigated through Mouse Hemophagocytic Synuclein (MH-S) cells.</p><p><strong>Results: </strong>The OPN level was found to be elevated in patients with sepsis (368.5 ± 249.4 ng/ml) compared to children with infections (73.78 ± 40.46 ng/ml) (p < 0.0001) and healthy individuals (44.03 ± 20.76 ng/ml) (p < 0.0001). The serum concentration of OPN was elevated in pediatric patients with septic shock compared to those with sepsis (504 ± 266.3 ng/ml vs. 238.6 ± 143.8 ng/ml, p < 0.001). Intravenous administration of OPN inhibitor into the tail vein decreased the mortality rate (HR = 0.2695, p = 0.0015), suppressed systemic inflammatory responses and mitigated lung tissue damage. The concentration of tumour necrosis factor (TNF)-α, IL-6 and IL-1β in serum of CLP mice treated with OPN inhibitor decreased compared with CLP mice. Within the sepsis mouse model, there was a marked increase in OPN expression in the lung's tissues compared to the sham group mice. This surge was accompanied by a significant accumulation of alveolar macrophages and an upregulation of inflammasome expression. Mechanistic investigations in MH-s cells revealed that OPN-siRNA suppressed the LPS-induced macrophage inflammatory response by inhibiting caspase1-dependent classical pyroptosis signaling pathway. However, recombinant OPN was supplemented after OPN silencing, the protective effects in MH-s cells treated with LPS were reversed.</p><p><strong>Conclusion: </strong>This study reveals that OPN has an adverse impact on the host's immune response to sepsis. Suppressing OPN expression holds potential therapeutic value for the treatment of sepsis.</p><p><strong>Trial registration: </strong>Study on the diagnostic value of osteopontin in children with sepsis. MR5024001771. Registered 22 January 2024. https//www.medicalresearch.org.cn.</p>","PeriodicalId":56120,"journal":{"name":"Journal of Inflammation-London","volume":"22 1","pages":"4"},"PeriodicalIF":4.4000,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763106/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inflammation-London","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12950-025-00430-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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Abstract
Background: Sepsis is a severe condition causing organ failure due to an abnormal immune reaction to infection, characterized by ongoing excessive inflammation and immune system issues. Osteopontin (OPN) is secreted by various cells and plays a crucial role in inflammatory responses and immune regulation. Nonetheless, the precise function of OPN in sepsis remains to be elucidated.
Methods: In the present study, we evaluated the levels of OPN in paediatric patients with sepsis and healthy individuals. We examined the impact of OPN on survival rates, systemic inflammation, and lung injury within an experimental sepsis model using cecal ligation and puncture (CLP). Furthermore, the pro-inflammatory effects and potential mechanisms of OPN in sepsis were investigated through Mouse Hemophagocytic Synuclein (MH-S) cells.
Results: The OPN level was found to be elevated in patients with sepsis (368.5 ± 249.4 ng/ml) compared to children with infections (73.78 ± 40.46 ng/ml) (p < 0.0001) and healthy individuals (44.03 ± 20.76 ng/ml) (p < 0.0001). The serum concentration of OPN was elevated in pediatric patients with septic shock compared to those with sepsis (504 ± 266.3 ng/ml vs. 238.6 ± 143.8 ng/ml, p < 0.001). Intravenous administration of OPN inhibitor into the tail vein decreased the mortality rate (HR = 0.2695, p = 0.0015), suppressed systemic inflammatory responses and mitigated lung tissue damage. The concentration of tumour necrosis factor (TNF)-α, IL-6 and IL-1β in serum of CLP mice treated with OPN inhibitor decreased compared with CLP mice. Within the sepsis mouse model, there was a marked increase in OPN expression in the lung's tissues compared to the sham group mice. This surge was accompanied by a significant accumulation of alveolar macrophages and an upregulation of inflammasome expression. Mechanistic investigations in MH-s cells revealed that OPN-siRNA suppressed the LPS-induced macrophage inflammatory response by inhibiting caspase1-dependent classical pyroptosis signaling pathway. However, recombinant OPN was supplemented after OPN silencing, the protective effects in MH-s cells treated with LPS were reversed.
Conclusion: This study reveals that OPN has an adverse impact on the host's immune response to sepsis. Suppressing OPN expression holds potential therapeutic value for the treatment of sepsis.
Trial registration: Study on the diagnostic value of osteopontin in children with sepsis. MR5024001771. Registered 22 January 2024. https//www.medicalresearch.org.cn.
期刊介绍：
Journal of Inflammation welcomes research submissions on all aspects of inflammation.
The five classical symptoms of inflammation, namely redness (rubor), swelling (tumour), heat (calor), pain (dolor) and loss of function (functio laesa), are only part of the story. The term inflammation is taken to include the full range of underlying cellular and molecular mechanisms involved, not only in the production of the inflammatory responses but, more importantly in clinical terms, in the healing process as well. Thus the journal covers molecular, cellular, animal and clinical studies, and related aspects of pharmacology, such as anti-inflammatory drug development, trials and therapeutic developments. It also considers publication of negative findings.
Journal of Inflammation aims to become the leading online journal on inflammation and, as online journals replace printed ones over the next decade, the main open access inflammation journal. Open access guarantees a larger audience, and thus impact, than any restricted access equivalent, and increasingly so, as the escalating costs of printed journals puts them outside University budgets. The unrestricted access to research findings in inflammation aids in promoting dynamic and productive dialogue between industrial and academic members of the inflammation research community, which plays such an important part in the development of future generations of anti-inflammatory therapies.
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