NMDAR Activation Attenuates the Protective Effect of BM-MSCs on Bleomycin-induced ALI Via the COX-2/PGE Pathway

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Jan 11

PMID 38205313

Authors

Xiao-Hong Li

Pu Huang

Hai-Peng Cheng

Yan Zhou

Dan-Dan Feng

Shao-Jie Yue

Yang Han

Zi-Qiang Luo

Affiliations

Soon will be listed here.

Abstract

N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation mediates glutamate (Glu) toxicity and involves bleomycin (BLM)-induced acute lung injury (ALI). We have reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) are NMDAR-regulated target cells, and NMDAR activation inhibits the protective effect of BM-MSCs on BLM-induced pulmonary fibrosis, but its effect on ALI remains unknown. Here, we found that Glu release was significantly elevated in plasma of mice at d 7 after intratracheally injected with BLM. BM-MSCs were pretreated with NMDA (the selective agonist of NMDAR) and transplanted into the recipient mice after the BLM challenge. BM-MSCs administration significantly alleviated the pathological changes, inflammatory response, myeloperoxidase activity, and malondialdehyde content in the damaged lungs, but NMDA-pretreated BM-MSCs did not ameliorate BLM-induced lung injury . Moreover, NMDA down-regulated prostaglandin E (PGE) secretion and cyclooxygenase (COX)-2 expression instead of COX-1 expression in BM-MSCs . We also found that NMDAR1 expression was increased and COX-2 expression was decreased, but COX-1 expression was not changed in primary BM-MSCs of BLM-induced ALI mice. Further, the cultured supernatants of lipopolysaccharide (LPS)-pretreated RAW264.7 macrophages were collected to detect inflammatory factors after co-culture with NMDA-pretreated BM-MSCs. The co-culture experiments showed that NMDA precondition inhibited the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation, and PGE could partially alleviate this inhibition. Our findings suggest that NMDAR activation attenuated the protective effect of BM-MSCs on BLM-induced ALI . NMDAR activation inhibited COX-2 expression and PGE secretion in BM-MSCs and weakened the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation . In conclusion, NMDAR activation attenuates the protective effect of BM-MSCs on BLM-induced ALI via the COX-2/PGE pathway. : Acute Lung Injury, BM-MSCs, NMDA receptor, COX-1/2, PGE.

References

Hodges R, Gisli Jenkins R, Wheeler-Jones C, Copeman D, Bottoms S, Bellingan G . Severity of lung injury in cyclooxygenase-2-deficient mice is dependent on reduced prostaglandin E(2) production. Am J Pathol. 2004; 165(5):1663-76. PMC: 1618657. DOI: 10.1016/S0002-9440(10)63423-2. View

Tang F, Yue S, Luo Z, Feng D, Wang M, Qian C . Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. Pediatr Pulmonol. 2005; 40(5):437-44. DOI: 10.1002/ppul.20299. View

Said S, Berisha H, Pakbaz H . Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1996; 93(10):4688-92. PMC: 39340. DOI: 10.1073/pnas.93.10.4688. View

Wang Y, Yue S, Luo Z, Cao C, Yu X, Liao Z . N-methyl-D-aspartate receptor activation mediates lung fibroblast proliferation and differentiation in hyperoxia-induced chronic lung disease in newborn rats. Respir Res. 2016; 17(1):136. PMC: 5075180. DOI: 10.1186/s12931-016-0453-1. View

Mosser D, Edwards J . Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12):958-69. PMC: 2724991. DOI: 10.1038/nri2448. View

Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M . Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014; 15:39. PMC: 3994204. DOI: 10.1186/1465-9921-15-39. View

Yu S, Liu L, Lv B, Che C, Fan D, Wang L . Inhibition of bleomycin-induced pulmonary fibrosis by bone marrow-derived mesenchymal stem cells might be mediated by decreasing MMP9, TIMP-1, INF-γ and TGF-β. Cell Biochem Funct. 2015; 33(6):356-66. DOI: 10.1002/cbf.3118. View

Aggarwal S, Pittenger M . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2004; 105(4):1815-22. DOI: 10.1182/blood-2004-04-1559. View

Kusuma G, Carthew J, Lim R, Frith J . Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling: Opportunities to Engineer the Therapeutic Effect. Stem Cells Dev. 2017; 26(9):617-631. DOI: 10.1089/scd.2016.0349. View

10.

Zhao Y, Yin L, Archer S, Lu C, Zhao G, Yao Y . Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. BMJ Open Respir Res. 2017; 4(1):e000183. PMC: 5531310. DOI: 10.1136/bmjresp-2017-000183. View

11.

Huang P, Zhou Y, Li X, Zhang Y, Cheng H, Fu J . N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence. Ann Transl Med. 2022; 10(11):642. PMC: 9263776. DOI: 10.21037/atm-22-2507. View

12.

Liang Z, Sun J, Wang P, Tian Q, Yang Z, Chen L . Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury. Chin Med J (Engl). 2011; 124(17):2715-22. View

13.

Spaggiari G, Abdelrazik H, Becchetti F, Moretta L . MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood. 2009; 113(26):6576-83. DOI: 10.1182/blood-2009-02-203943. View

14.

Gu W, Song L, Li X, Wang D, Guo X, Xu W . Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways. Sci Rep. 2015; 5:8733. PMC: 4348625. DOI: 10.1038/srep08733. View

15.

Crisostomo P, Wang Y, Markel T, Wang M, Lahm T, Meldrum D . Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. Am J Physiol Cell Physiol. 2008; 294(3):C675-82. DOI: 10.1152/ajpcell.00437.2007. View

16.

Sercundes M, Ortolan L, Debone D, Soeiro-Pereira P, Gomes E, Aitken E . Correction: Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice. PLoS Pathog. 2017; 13(11):e1006730. PMC: 5687700. DOI: 10.1371/journal.ppat.1006730. View

17.

Wang M, Luo Z, Liu S, Li L, Deng X, Huang F . Glutamate mediates hyperoxia-induced newborn rat lung injury through N-methyl-D-aspartate receptors. Am J Respir Cell Mol Biol. 2008; 40(3):260-7. DOI: 10.1165/rcmb.2008-0135OC. View

18.

Rojas M, Xu J, Woods C, Mora A, Spears W, Roman J . Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005; 33(2):145-52. PMC: 2715309. DOI: 10.1165/rcmb.2004-0330OC. View

19.

Huang X, Xiu H, Zhang S, Zhang G . The Role of Macrophages in the Pathogenesis of ALI/ARDS. Mediators Inflamm. 2018; 2018:1264913. PMC: 5989173. DOI: 10.1155/2018/1264913. View

20.

Lalu M, Moher D, Marshall J, Fergusson D, Mei S, Macleod M . Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol. Syst Rev. 2014; 3:48. PMC: 4046388. DOI: 10.1186/2046-4053-3-48. View