<em>LCMR1</em> deficiency exacerbates LPS‑induced lung injury in lung‑on‑a‑chip and mouse models

Mo,Zhenfei; Su,Chengcheng; Liu,Jinxia; Ren,Jiabo; Liu,Lu; Wang,Yueming; Li,Yanqin; Li,Chunsun; Yang,Zhen; Ma,Xiuqing; Chen,Liangan

doi:10.3892/mmr.2025.13554

LCMR1 deficiency exacerbates LPS‑induced lung injury in lung‑on‑a‑chip and mouse models

Authors:
- Zhenfei Mo
- Chengcheng Su
- Jinxia Liu
- Jiabo Ren
- Lu Liu
- Yueming Wang
- Yanqin Li
- Chunsun Li
- Zhen Yang
- Xiuqing Ma
- Liangan Chen
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Affiliations: Medical School of Chinese People's Liberation Army, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Department of Nutrition, The First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Department of Pulmonary and Critical Care Medicine, The Eighth Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Department of Pulmonary and Critical Care Medicine, The First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
Published online on: May 2, 2025 https://doi.org/10.3892/mmr.2025.13554
Article Number: 189
Copyright: © Mo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The oncogene lung cancer metastasis‑related protein 1 (LCMR1) is associated with neoplastic diseases and LCMR1 conditional knockout affects cell homeostasis. In the present study, the role of LCMR1 in lipopolysaccharide (LPS)‑induced acute lung injury (ALI) was investigated. Firstly, wild‑type C57BL/6 mice were used to establish an LPS‑induced ALI model via intratracheal injection of LPS, and the expression of LCMR1 was examined at 24, 48, 72 and 96 h after injury. The LPS‑induced lung injury model was subsequently constructed in mice with conditional knockout of LCMR1 in type II alveolar epithelial cells (AEC‑II). Subsequently, histopathological analysis, lung wet/dry weight ratio comparisons and lung function tests were performed; survival rates after LPS challenge of the conditional knockout mice were measured; bronchoalveolar lavage fluid (BALF) was collected, and the concentrations of protein and inflammatory cytokines in BALF were measured; and transmission electron microscopy of lung tissue was conducted to evaluate the degree of lung injury. To further investigate the mechanism, a lung‑on‑a‑chip model with overexpression or knockdown of LCMR1 was constructed to simulate the alveolar environment under LPS treatment. The expression levels of E‑cadherin and pro‑pulmonary surfactant C precursor (proSP‑C) in the chips were determined by immunofluorescence, and the integrity of the air‑blood barrier was analyzed using a permeability assay. In the mouse model, LCMR1 expression was downregulated in wild‑type mice with LPS‑induced lung injury. LCMR1 conditional knockout in AEC‑II caused increased mortality, impaired lung function, aggravated pathological damage and increased the inflammatory response in mice with LPS‑induced ALI. Furthermore, in the lung‑on‑a‑chip model, LCMR1 knockdown reduced the expression of E‑cadherin and proSP‑C, and impaired the air‑blood barrier function, whereas LCMR1 overexpression attenuated these effects, which may be related to cell differentiation dysfunction and enhanced apoptosis. In conclusion, the present study revealed that LCMR1 deficiency may exacerbate LPS‑induced ALI and could be considered a novel target for intervention in ALI.

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1	Long ME, Mallampalli RK and Horowitz JC: Pathogenesis of pneumonia and acute lung injury. Clin Sci (Lond). 136:747–769. 2022. View Article : Google Scholar : PubMed/NCBI
2	Wick KD, Ware LB and Matthay MA: Acute respiratory distress syndrome. BMJ. 387:e0766122024. View Article : Google Scholar : PubMed/NCBI
3	Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, et al: Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 315:788–800. 2016. View Article : Google Scholar : PubMed/NCBI
4	Liu H, Yu X, Yu S and Kou J: Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Int Immunopharmacol. 29:937–946. 2015. View Article : Google Scholar : PubMed/NCBI
5	Bos LDJ and Ware LB: Acute respiratory distress syndrome: Causes, pathophysiology, and phenotypes. Lancet. 400:1145–1156. 2022. View Article : Google Scholar : PubMed/NCBI
6	Wang Y, Wang L, Ma S, Cheng L and Yu G: Repair and regeneration of the alveolar epithelium in lung injury. FASEB J. 38:e236122024. View Article : Google Scholar : PubMed/NCBI
7	Woods SJ, Waite AA, O'Dea KP, Halford P, Takata M and Wilson MR: Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol. 308:L912–L921. 2015. View Article : Google Scholar : PubMed/NCBI
8	Li N, Liu B, Xiong R, Li G, Wang B and Geng Q: HDAC3 deficiency protects against acute lung injury by maintaining epithelial barrier integrity through preserving mitochondrial quality control. Redox Biol. 63:1027462023. View Article : Google Scholar : PubMed/NCBI
9	Chen H, Lin X, Yi X, Liu X, Yu R, Fan W, Ling Y, Liu Y and Xie W: SIRT1-mediated p53 deacetylation inhibits ferroptosis and alleviates heat stress-induced lung epithelial cells injury. Int J Hyperthermia. 39:977–986. 2022. View Article : Google Scholar : PubMed/NCBI
10	Hiemstra PS, Tetley TD and Janes SM: Airway and alveolar epithelial cells in culture. Eur Respir J. 54:19007422019. View Article : Google Scholar : PubMed/NCBI
11	Perelson AS and Ribeiro RM: Introduction to modeling viral infections and immunity. Immunol Rev. 285:5–8. 2018. View Article : Google Scholar : PubMed/NCBI
12	Ma C, Peng Y, Li H and Chen W: Organ-on-a-Chip: A new paradigm for drug development. Trends Pharmacol Sci. 42:119–133. 2021. View Article : Google Scholar : PubMed/NCBI
13	Tan J, Guo Q, Tian L, Pei Z, Li D, Wu M, Zhang J and Gao X: Biomimetic lung-on-a-chip to model virus infection and drug evaluation. Eur J Pharm Sci. 180:1063292023. View Article : Google Scholar : PubMed/NCBI
14	Bai H, Si L, Jiang A, Belgur C, Zhai Y, Plebani R, Oh CY, Rodas M, Patil A, Nurani A, et al: Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip. Nat Commun. 13:19282022. View Article : Google Scholar : PubMed/NCBI
15	Nawroth JC, Lucchesi C, Cheng D, Shukla A, Ngyuen J, Shroff T, Varone A, Karalis K, Lee HH, Alves S, et al: A microengineered airway lung chip models key features of Viral-induced exacerbation of asthma. Am J Respir Cell Mol Biol. 63:591–600. 2020. View Article : Google Scholar : PubMed/NCBI
16	Wang P, Jin L, Zhang M, Wu Y, Duan Z, Guo Y, Wang C, Guo Y, Chen W, Liao Z, et al: Blood-brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung-brain microphysiological system. Nat Biomed Eng. 8:1053–1068. View Article : Google Scholar : PubMed/NCBI
17	Chen L, Liang Z, Tian Q, Li C, Ma X, Zhang Y, Yang Z, Wang P and Li Y: Overexpression of LCMR1 is significantly associated with clinical stage in human NSCLC. J Exp Clin Cancer Res. 30:182011. View Article : Google Scholar : PubMed/NCBI
18	Wang Y, Li C, Wu Z, Dai Y, Liu L and Chen L: Deletion of LCMR1 in alveolar type II cells induces lethal impairment of lung structure and function in adult mice. J Thorac Dis. 15:1445–1459. 2023. View Article : Google Scholar : PubMed/NCBI
19	Bao X, Zhao L, Guan H and Li F: Inhibition of LCMR1 and ATG12 by demethylation-activated miR-570-3p is involved in the anti-metastasis effects of metformin on human osteosarcoma. Cell Death Dis. 9:6112018. View Article : Google Scholar : PubMed/NCBI
20	Wang K, Wang X, Fu X, Sun J, Zhao L, He H and Fan Y: Lung cancer metastasis-related protein 1 promotes the transferring from advanced metastatic prostate cancer to castration-resistant prostate cancer by activating the glucocorticoid receptor alpha signal pathway. Bioengineered. 13:5373–5385. 2022. View Article : Google Scholar : PubMed/NCBI
21	Liu L, Li C, Wu Z, Li Y, Yu H, Li T, Wang Y, Zhao W and Chen L: LCMR1 promotes Large-cell lung cancer proliferation and metastasis by downregulating HLA-Encoding genes. Cancers (Basel). 15:54452023. View Article : Google Scholar : PubMed/NCBI
22	Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, et al: The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 18:e30004102020. View Article : Google Scholar : PubMed/NCBI
23	Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK and Mele T: A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 7:2332014. View Article : Google Scholar : PubMed/NCBI
24	Stanojevic S, Kaminsky DA, Miller MR, Thompson B, Aliverti A, Barjaktarevic I, Cooper BG, Culver B, Derom E, Hall GL, et al: ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J. 60:21014992022. View Article : Google Scholar : PubMed/NCBI
25	Glaab T, Taube C, Braun A and Mitzner W: Invasive and noninvasive methods for studying pulmonary function in mice. Respir Res. 8:632007. View Article : Google Scholar : PubMed/NCBI
26	Fukumoto J, Fukumoto I, Parthasarathy PT, Cox R, Huynh B, Ramanathan GK, Venugopal RB, Allen-Gipson DS, Lockey RF and Kolliputi N: NLRP3 deletion protects from hyperoxia-induced acute lung injury. Am J Physiol Cell Physiol. 305:C182–C189. 2013. View Article : Google Scholar : PubMed/NCBI
27	Zhang M, Wang P, Luo R, Wang Y, Li Z, Guo Y, Yao Y, Li M, Tao T, Chen W, et al: Biomimetic human disease model of SARS-CoV-2-Induced lung injury and immune responses on organ chip system. Adv Sci (Weinh). 8:20029282021. View Article : Google Scholar : PubMed/NCBI
28	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
29	Agaesse G, Barbollat-Boutrand L, Sulpice E, Bhajun R, El Kharbili M, Berthier-Vergnes O, Degoul F, de la Fouchardière A, Berger E, Voeltzel T, et al: A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. Oncogene. 36:50842017. View Article : Google Scholar : PubMed/NCBI
30	Wang L, Wang X, Tong L, Wang J, Dou M, Ji S, Bi J, Chen C, Yang D, He H, et al: Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells. Scand J Immunol. 88:e127152018. View Article : Google Scholar : PubMed/NCBI
31	Dasgupta Q, Jiang A, Wen AM, Mannix RJ, Man Y, Hall S, Javorsky E and Ingber DE: A human lung alveolus-on-a-chip model of acute radiation-induced lung injury. Nat Commun. 14:65062023. View Article : Google Scholar : PubMed/NCBI
32	Sehlmeyer K, Ruwisch J, Roldan N and Lopez-Rodriguez E: Alveolar dynamics and Beyond-The importance of surfactant protein C and cholesterol in lung homeostasis and fibrosis. Front Physiol. 11:3862020. View Article : Google Scholar : PubMed/NCBI
33	Xiao K, He W, Guan W, Hou F, Yan P, Xu J, Zhou T, Liu Y and Xie L: Mesenchymal stem cells reverse EMT process through blocking the activation of NF-κB and Hedgehog pathways in LPS-induced acute lung injury. Cell Death Dis. 11:8632020. View Article : Google Scholar : PubMed/NCBI
34	Li J, Deng SH, Li J, Li L, Zhang F, Zou Y, Wu DM and Xu Y: Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses. Cell Mol Biol Lett. 27:292022. View Article : Google Scholar : PubMed/NCBI
35	Zhang Y, Qin P, Tian L, Yan J and Zhou Y: The role of mediator complex subunit 19 in human diseases. Exp Biol Med (Maywood). 246:1681–1687. 2021. View Article : Google Scholar : PubMed/NCBI
36	Zhang X, Fan Y, Liu B, Qi X, Guo Z and Li L: Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression. Breast Cancer. 24:433–441. 2017. View Article : Google Scholar : PubMed/NCBI
37	Zhang X, Gao D, Fang K, Guo Z and Li L: Med19 is targeted by miR-101-3p/miR-422a and promotes breast cancer progression by regulating the EGFR/MEK/ERK signaling pathway. Cancer Lett. 444:105–115. 2019. View Article : Google Scholar : PubMed/NCBI
38	Ruoff R, Weber H, Wang Y, Huang H, Shapiro E, Fenyo D and Garabedian MJ: MED19 encodes two unique protein isoforms that confer prostate cancer growth under low androgen through distinct gene expression programs. Sci Rep. 13:182272023. View Article : Google Scholar : PubMed/NCBI
39	Liu K, Meng X, Liu Z, Tang M, Lv Z, Huang X, Jin H, Han X, Liu X, Pu W, et al: Tracing the origin of alveolar stem cells in lung repair and regeneration. Cell. 187:2428–2445.e20. 2024. View Article : Google Scholar : PubMed/NCBI
40	Kaiser AM, Gatto A, Hanson KJ, Zhao RL, Raj N, Ozawa MG, Seoane JA, Bieging-Rolett KT, Wang M, Li I, et al: p53 governs an AT1 differentiation programme in lung cancer suppression. Nature. 619:851–859. 2023. View Article : Google Scholar : PubMed/NCBI
41	Xu Y, Liang Z, Li C, Yang Z and Chen L: LCMR1 interacts with DEK to suppress apoptosis in lung cancer cells. Mol Med Rep. 16:4159–4164. 2017. View Article : Google Scholar : PubMed/NCBI
42	Zhang Y, Li P, Hu J, Zhao LN, Li JP, Ma R, Li WW, Shi M and Wei LC: Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance. Biochem Biophys Res Commun. 508:210–216. 2019. View Article : Google Scholar : PubMed/NCBI