Potential pharmaceuticals targeting neuroimmune interactions in treating acute lung injury

Abstract

	•The lungs present abundant nerve innervations.
	•Neuroimmune interactions exert a modulatory effect in the onset and progression of lung inflammatory diseases, especially acute lung injury.
	•The advancements of potential drugs for ALI targeting neuroimmune crosstalk at different stages from preclinical investigation to clinical trials are elaborated.
	•Point out the direction for the development of neuroimmune pharmacology in the future.

Keywords

acute lung injury / airway innervation / inflammation / neuroimmune interaction / potential pharmaceuticals

References

[1] Bernard G, Artigas A, Brigham K, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818-824.

[2] Trillo-Alvarez C, Cartin-Ceba R, Kor D, et al. Acute lung injury prediction score: derivation and validation in a population-based sample. Eur Respir J. 2011;37(3):604-609.

[3] Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788-800.

[4] Pisani L, Algera AG, Serpa Neto A, et al. Epidemiological characteristics, ventilator management, and clinical outcome in patients receiving invasive ventilation in intensive care units from 10 Asian Middle-Income Countries (PRoVENT-iMiC):an international, multicenter, prospective study. Am J Trop Med Hyg. 2021;104(3):1022-1033.

[5] Ruhl AP, Lord RK, Panek JA, et al. Health care resource use and costs of two-year survivors of acute lung injury. An observational cohort study. Ann Am Thorac Soc. 2015;12(3):392-401.

[6] Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18.

[7] Mannes PZ, Barnes CE, Latoche JD, et al. 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography to monitor lung inflammation and therapeutic response to dexamethasone in a murine model of acute lung injury. Mol Imaging Biol. 2023;25(4):681-691.

[8] Bellani G, Messa C, Guerra L, et al. Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: a [18F]-fluoro-2-deoxy-D-glucose PET/CT study. Crit Care Med. 2009;37(7):2216-2222.

[9] Wang K, Rong G, Gao Y, et al. Fluorous-tagged peptide nanoparticles ameliorate acute lung injury via lysosomal stabilization and inflammation inhibition in pulmonary macrophages. Small. 2022;18(40):e2203432.

[10] Meng L, Liao X, Wang Y, et al. Pharmacologic therapies of ARDS: from natural herb to nanomedicine. Front Pharmacol. 2022;13:930593.

[11] Gorman E, O’Kane C, McAuley D. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management. Lancet. 2022;400(10358):1157-1170.

[12] Chu C, Artis D, Chiu IM. Neuro-immune Interactions in the Tissues. Immunity. 2020;52(3):464-474.

[13] Kabata H, Artis D. Neuro-immune crosstalk and allergic inflammation. J Clin Invest. 2019;129(4):1475-1482.

[14] Mack MR, Kim BS. The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 2018;39(12):980-991.

[15] Li R, Hu X, Chen H, et al. Role of cholinergic anti-inflammatory pathway in protecting sepsis-induced acute lung injury through regulation of the conventional dendritic cells. Mediators Inflamm. 2022;2022:1474891.

[16] Andersson U. The cholinergic anti-inflammatory pathway alleviates acute lung injury. Mol Med. 2020;26(1):64.

[17] Sano M, Tsubone H, Sugano S. Vagal afferent activities and respiratory reflexes during drug-induced bronchoconstriction in the guinea pig. J Vet Med Sci. 1992;54(5):989-998.

[18] Ford AP, Undem BJ, Birder LA, Grundy D, Pijacka W, Paton JF. P2×3 receptors and sensitization of autonomic reflexes. Auton Neurosci. 2015;191:16-24.

[19] Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ. P2×2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol. 2008;295(5):L858-L865.

[20] Mei N, Condamin M, Boyer A. The composition of the vagus nerve of the cat. Cell Tissue Res. 1980;209(3):423-431.

[21] Verhein KC, Fryer AD, Jacoby DB. Neural control of airway inflammation. Curr Allergy Asthma Rep. 2009;9(6):484-490.

[22] Lukas RJ, Changeux JP, Le Novère N, et al. International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol Rev. 1999;51(2):397-401.

[23] Kummer W, Krasteva-Christ G. Non-neuronal cholinergic airway epithelium biology. Curr Opin Pharmacol. 2014;16:43-49.

[24] Potenzieri C, Meeker S, Undem BJ. Activation of mouse bronchopulmonary C-fibres by serotonin and allergen-ovalbumin challenge. J Physiol. 2012;590(21):5449-5459.

[25] Chuaychoo B, Lee MG, Kollarik M, Undem BJ. Effect of 5-hydroxytryptamine on vagal C-fiber subtypes in guinea pig lungs. Pulm Pharmacol Ther. 2005;18(4):269-276.

[26] Coleridge HM, Coleridge JC, Roberts AM. Rapid shallow breathing evoked by selective stimulation of airway C fibres in dogs. J Physiol. 1983;340:415-433.

[27] Burnstock G. Purine and purinergic receptors. Brain Neurosci Adv. 2018;2:2398212818817494.

[28] Lukashev D, Smith P, Caldwell C, Ohta A, Apasov S, Sitkovsky M. Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs. Biochem Pharmacol. 2003;65(12):2081-2090.

[29] Cagnina R, Ramos S, Marshall M, Wang G, Frazier C, Linden J. Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2009;297(3):L467-L474.

[30] Yang D, Koupenova M, McCrann D, et al. The A2b adenosine receptor protects against vascular injury. Proc Nat Acad Sci USA. 2008;105(2):792-796.

[31] Yang D, Zhang Y, Nguyen H, et al. The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest. 2006;116(7):1913-1923.

[32] Antonioli L, Blandizzi C, Pacher P, Haskó G. The purinergic system as a pharmacological target for the treatment of immune-mediated inflammatory diseases. Pharmacol Rev. 2019;71(3):345-382.

[33] Nassenstein C, Taylor-Clark TE, Myers AC, et al. Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J Physiol. 2010;588(Pt. 23):4769-4783.

[34] McGovern AE, Davis-Poynter N, Yang SK, Simmons DG, Farrell MJ, Mazzone SB. Evidence for multiple sensory circuits in the brain arising from the respiratory system: an anterograde viral tract tracing study in rodents. Brain Struct Funct. 2015;220(6):3683-3699.

[35] McGovern AE, Driessen AK, Simmons DG, et al. Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system. J Neurosci. 2015;35(18):7041-7055.

[36] Wilson CG, Zhang Z, Bonham AC. Non-NMDA receptors transmit cardiopulmonary C fibre input in nucleus tractus solitarii in rats. J Physiol. 1996;496(Pt. 3):773-785.

[37] Hallberg M. Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors. Med Res Rev. 2015;35(3):464-519.

[38] Calixto JB, Medeiros R, Fernandes ES, Ferreira J, Cabrini DA, Campos MM. Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol. 2004;143(7):803-818.

[39] Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem. 2004;73:953-990.

[40] Stornetta RL, Hawelu-Johnson CL, Guyenet PG, Lynch KR. Astrocytes synthesize angiotensinogen in brain. Science. 1988;242(4884):1444-1446.

[41] Kawasaki H, Takasaki K, Furukawa T. Exaggerated pressor response to centrally administered renin in freely moving, spontaneously hypertensive rats. Eur J Pharmacol. 1987;138(3):351-357.

[42] Balakumar P, Jagadeesh G. A century old renin-angiotensin system still grows with endless possibilities: aT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signalling. 2014;26(10):2147-2160.

[43] Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens. 2007;21(1):20-27.

[44] Strawn WB, Ferrario CM. Mechanisms linking angiotensin II and atherogenesis. Curr Opin Lipidol. 2002;13(5):505-512.

[45] Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020;382(17):1653-1659.

[46] Haxhiu MA, Jansen AS, Cherniack NS, Loewy AD. CNS innervation of airway-related parasympathetic preganglionic neurons: a transneuronal labeling study using pseudorabies virus. Brain Res. 1993;618(1):115-134.

[47] Hadziefendic S, Haxhiu MA. CNS innervation of vagal preganglionic neurons controlling peripheral airways: a transneuronal labeling study using pseudorabies virus. J Auton Nerv Syst. 1999;76(2-3):135-145.

[48] Barnes PJ. Neural mechanisms in asthma. Br Med Bull. 1992;48(1):149-168.

[49] Kummer W, Fischer A, Kurkowski R, Heym C. The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry. Neuroscience. 1992;49(3):715-737.

[50] Uddman R, Sundler F, Emson P. Occurrence and distribution of neuropeptide-Y-immunoreactive nerves in the respiratory tract and middle ear. Cell Tissue Res. 1984;237(2):321-327.

[51] Partanen M, Laitinen A, Hervonen A, Toivanen M, Laitinen LA. Catecholamine-and acetylcholinesterase-containing nerves in human lower respiratory tract. Histochemistry. 1982;76(2):175-188.

[52] Baral P, Umans BD, Li L, et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat Med. 2018;24(4):417-426.

[53] Abdullah H, Heaney LG, Cosby SL, McGarvey LP. Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax. 2014;69(1):46-54.

[54] Gao Z, Li L, Huang Y, et al. Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection. Acta Pharmacol Sin. 2021;42(10):1642-1652.

[55] Verzele N, Chua B, Law C, et al. The impact of influenza pulmonary infection and inflammation on vagal bronchopulmonary sensory neurons. FASEB J. 2021;35(3):e21320.

[56] Grebe K, Takeda K, Hickman H, et al. Cutting edge: sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza A virus pathogenesis. J Immunol. 2010;184(2):540-544.

[57] Xia S, Liu M, Wang C, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 2020;30(4):343-355.

[58] Gressens SB, Leftheriotis G, Dussaule JC, Flamant M, Levy BI, Vidal-Petiot E. Controversial roles of the renin angiotensin system and its modulators during the COVID-19 pandemic. Front Physiol. 2021;12:624052.

[59] Tu WJ, Melino M, Dunn J, et al. In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting. Nat Commun. 2023;14(1):3680.

[60] Erfinanda L, Ravindran K, Kohse F, et al. Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation. Eur Respir J. 2021;57(1):2000921.

[61] Baral P, Udit S, Chiu IM. Pain and immunity: implications for host defence. Nat Rev Immunol. 2019;19(7):433-447.

[62] Nagashima H, Mahlakõiv T, Shih HY, et al. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity. 2019;51(4):682-695. e6.

[63] Wallrapp A, Burkett PR, Riesenfeld SJ, et al. Calcitonin gene-related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses. Immunity. 2019;51(4):709-723. e6.

[64] Rochlitzer S, Veres TZ, Kühne K, et al. The neuropeptide calcitonin gene-related peptide affects allergic airway inflammation by modulating dendritic cell function. Clin Exp Allergy. 2011;41(11):1609-1621.

[65] Nussbaum JC, Van Dyken SJ, von Moltke J, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013;502(7470):245-248.

[66] Talbot S, Abdulnour RE, Burkett PR, et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron. 2015;87(2):341-354.

[67] Dragunas G, Woest ME, Nijboer S, et al. Cholinergic neuroplasticity in asthma driven by TrkB signaling. FASEB J. 2020;34(6):7703-7717.

[68] Moriyama S, Brestoff JR, Flamar AL, et al. β(2)-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science. 2018;359(6379):1056-1061.

[69] Wang W, Cohen JA, Wallrapp A, et al. Age-related dopaminergic innervation augments T helper 2-type allergic inflammation in the postnatal lung. Immunity. 2019;51(6):1102-1118. e7.

[70] Belvisi M, Birrell M, Khalid S, et al. Neurophenotypes in airway diseases. Insights from translational cough studies. Am J Respir Crit Care Med. 2016;193(12):1364-1372.

[71] Pelleg A, Schulman E. Adenosine 5’-triphosphate axis in obstructive airway diseases. Am J Ther. 2002;9(5):454-464.

[72] Schneider S, Merfort I, Idzko M, Zech A. Blocking P2X purinoceptor 4 signalling alleviates cigarette smoke induced pulmonary inflammation. Respir Res. 2022;23(1):148.

[73] Douaoui S, Djidjik R, Boubakeur M, et al. GTS-21, an α7nAChR agonist, suppressed the production of key inflammatory mediators by PBMCs that are elevated in COPD patients and associated with impaired lung function. Immunobiology. 2020;225(3):151950.

[74] Mandal J, Roth M, Costa L, et al. Vasoactive intestinal peptide for diagnosing exacerbation in chronic obstructive pulmonary disease. Respiration. 2015;90(5):357-368.

[75] Burian B, Storka A, Nadler B, Petkov V, Block L. Inhaled vasoactive intestinal peptide (VIP) improves the 6-minute walk test and quality of life in patients with COPD: the VIP/COPD-trial. Chest J. 2006;130:121S.

[76] Xu H, Zhao M, Wang X. [Changes of calcitonin gene-related peptide content in induced sputum from patients with COPD and asthma]. Zhonghua Jie He He Hu Xi Za Zhi. 1999;22(9):558-561.

[77] Boschetto P, Miotto D, Bononi I, et al. Sputum substance P and neurokinin A are reduced during exacerbations of chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2005;18(3):199-205.

[78] Kneussl M, Kummer F. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Med. 1984;311(21):1379-1380.

[79] Kistemaker L, Bos I, Hylkema M, et al. Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice. Eur Respir J. 2013;42(6):1677-1688.

[80] Chhabra S, Gupta M, Ramaswamy S, Dash D, Bansal V, Deepak K. Cardiac sympathetic dominance and systemic inflammation in COPD. COPD. 2015;12(5):552-559.

[81] Haarmann H, Mohrlang C, Tschiesner U, et al. Inhaled β-agonist does not modify sympathetic activity in patients with COPD. BMC Pulm Med. 2015;15(1):46.

[82] Zanos TP, Silverman HA, Levy T, et al. Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity. Proc Nat Acad Sci USA. 2018;115(21):E4843-E4852.

[83] Vida G, Peña G, Deitch EA, Ulloa L. α7-cholinergic receptor mediates vagal induction of splenic norepinephrine. J Immunol. 2011;186(7):4340-4346.

[84] Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98-101.

[85] dos Santos CC, Shan Y, Akram A, Slutsky AS, Haitsma JJ. Neuroimmune regulation of ventilator-induced lung injury. Am J Respir Crit Care Med. 2011;183(4):471-482.

[86] Han X. Inhibiting P2Y12 receptor relieves LPS-induced inflammation and endothelial dysfunction. Immun Inflamm Dis. 2022;10(10):e697.

[87] El Mdawar M, Maître B, Magnenat S, Gachet C, Hechler B, de la Salle H. The ATP-gated P2X ion channel contributes to the severity of antibody-mediated transfusion-related acute lung injury in mice. Sci Rep. 2019;9(1):5159.

[88] Wang S, Zhao J, Wang H, Liang Y, Yang N, Huang Y. Blockage of P2×7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome. Int Immunopharmacol. 2015;27(1):38-45.

[89] Cong Z, Li D, Tao Y, Lv X, Zhu X. α -AR antagonism by BRL-44408 maleate attenuates acute lung injury in rats with downregulation of ERK1/2, p38MAPK, and p65 pathway. J Cell Physiol. 2020;235(10):6905-6914.

[90] Zhang L, Nie Y, Zheng Y, et al. Esmolol attenuates lung injury and inflammation in severe acute pancreatitis rats. Pancreatology. 2016;16(5):726-732.

[91] Matsuishi Y, Jesmin S, Kawano S, et al. Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1. Life Sci. 2016;166:27-33.

[92] Bosmann M, Grailer J, Zhu K, et al. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. FASEB J. 2012;26(5):2137-2144.

[93] Zhou Y, Zhang C, Duan J, et al. Vasoactive intestinal peptide suppresses the NLRP3 inflammasome activation in lipopolysaccharide-induced acute lung injury mice and macrophages. Biomed Pharmacother. 2020;121:109596.

[94] Ran WZ, Dong L, Tang CY, et al. Vasoactive intestinal peptide suppresses macrophage-mediated inflammation by downregulating interleukin-17A expression via PKA-and PKC-dependent pathways. Int J Exp Pathol. 2015;96(4):269-275.

[95] Yang W, Xv M, Yang W, Wang N, Zhang X, Li W. Exogenous α-calcitonin gene-related peptide attenuates lipopolysaccharide-induced acute lung injury in rats. Mol Med Rep. 2015;12(2):2181-2188.

[96] Lange M, Enkhbaatar P, Traber D, et al. Role of calcitonin gene-related peptide (CGRP) in ovine burn and smoke inhalation injury. J Appl Physiol (1985). 2009;107(1):176-184.

[97] Hong-Min F, Chun-Rong H, Rui Z, Li-Na S, Ya-Jun W, Li L. CGRP 8–37 enhances lipopolysaccharide-induced acute lung injury and regulating aquaporin 1 and 5 expressions in rats. J Physiol Biochem. 2016;73(3):381-386.

[98] Pinheiro NM, Banzato R, Tibério I, et al. Acute lung injury in cholinergic-deficient mice supports anti-inflammatory role of α7 nicotinic acetylcholine receptor. Int J Mol Sci. 2021;22(14):7552.

[99] Goto D, Nagata S, Naito Y, et al. Nicotinic acetylcholine receptor agonist reduces acute lung injury after renal ischemia-reperfusion injury by acting on splenic macrophages in mice. Am J Physiol Renal Physiol. 2022;322(5):F540-F552.

[100] Kox M, Pompe JC, Peters E, et al. α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-α production and lung injury. Br J Anaesth. 2011;107(4):559-566.

[101] Su X, Matthay MA, Malik AB. Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol. 2010;184(1):401-410.

[102] Ma P, Yu K, Yu J, et al. Effects of nicotine and vagus nerve in severe acute pancreatitis-associated lung injury in rats. Pancreas. 2016;45(4):552-560.

[103] Sitapara RA, Gauthier AG, Valdés-Ferrer SI, et al. The α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuates hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation. Mol Med. 2020;26(1):63.

[104] Li G, Zhou CL, Zhou QS, Zou HD. Galantamine protects against lipopolysaccharide-induced acute lung injury in rats. Braz J Med Biol Res. 2016;49(2):e5008.

[105] Zhang X, Wei X, Deng Y, et al. Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway. Signal Transduct Target Ther. 2022;7(1):307.

[106] Yuan Q, Xiao F, Liu Q, et al. M(3) receptor is involved in the effect of penehyclidine hydrochloride reduced endothelial injury in LPS-stimulated human pulmonary microvascular endothelial cell. Pulm Pharmacol Ther. 2018;48:144-150.

[107] Shen W, Gan J, Xu S, Jiang G, Wu H. Penehyclidine hydrochloride attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Pharmacol Res. 2009;60(4):296-302.

[108] Xu ZP, Yang K, Xu GN, et al. Role of M3 mAChR in in vivo and in vitro models of LPS-induced inflammatory response. Int Immunopharmacol. 2012;14(3):320-327.

[109] Zhang Y, Jia S, Gao T, Zhang R, Liu Z, Wang Y. Dexmedetomidine mitigate acute lung injury by inhibiting IL-17-induced inflammatory reaction. Immunobiology. 2018;223(1):32-37.

[110] Jiang Y, Xia M, Xu J, Huang Q, Dai Z, Zhang X. Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury. Immunol Res. 2021;69(2):162-175.

[111] Jiang Y, Dai Z, Zhang X, Zhao W, Huang Q, Gao L. Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide. J Huazhong Univ Sci Technolog Med Sci. 2015;35(5):684-688.

[112] Zhang Y, Wang X, Liu Z, Yu L. Dexmedetomidine attenuates lipopolysaccharide induced acute lung injury by targeting NLRP3 via miR-381. J Biochem Mol Toxicol. 2018;32(11):e22211.

[113] Chen Y, Huang Y, Xiong B, Luo H, Song X. Dexmedetomidine ameliorates renal ischemia reperfusion-mediated activation of the NLRP3 inflammasome in alveolar macrophages. Gene. 2020;758:144973.

[114] Chen Q, Yi B, Ma J, et al. α2-adrenoreceptor modulated FAK pathway induced by dexmedetomidine attenuates pulmonary microvascular hyper-permeability following kidney injury. Oncotarget. 2016;7(35):55990-56001.

[115] Zhang Y, Tan X, Xue L. The alpha2-adrenoreceptor agonist dexmedetomidine protects against lipopolysaccharide-induced apoptosis via inhibition of gap junctions in lung fibroblasts. Biochem Biophys Res Commun. 2018;495(1):92-97.

[116] Song Q, Lin L, Chen L, Cheng L, Zhong W. Co-administration of N-acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS-induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance. Clin Exp Pharmacol Physiol. 2020;47(2):294-301.

[117] Ji M, Zhu X, Liu F, et al. Alpha 2A-adrenoreceptor blockade improves sepsis-induced acute lung injury accompanied with depressed high mobility group box-1 levels in rats. Cytokine. 2012;60(3):639-645.

[118] Robriquet L, Kipnis E, Guery B. Beta-adrenergic modulation of lung fluid balance in acute P aeruginosa pneumonia in rats. Exp Lung Res. 2011;37(8):453-460.

[119] Lakshminarayana PH, Kahn JM. First do no harm: surrogate endpoints and the lesson of β-agonists in acute lung injury. Crit Care. 2012;16(3):314.

[120] Matthay M, Brower R, Carson S, et al. Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184(5):561-568.

[121] Perkins GD, Gates S, Park D, et al. The beta agonist lung injury trial prevention. A randomized controlled trial. Am J Respir Crit Care Med. 2014;189(6):674-683.

[122] Perkins G, Park D, Alderson D, et al. The Beta Agonist Lung Injury TrIal (BALTI)–prevention trial protocol. Trials. 2011;12:79.

[123] Meng L, Wang M, Gao Y, et al. Dopamine D1 receptor agonist alleviates acute lung injury via modulating inflammatory responses in macrophages and barrier function in airway epithelial cells. Free Radical Biol Med. 2023;202:2-16.

[124] Jiang W, Li M, He F, et al. Dopamine D1 receptor agonist A-68930 inhibits NLRP3 inflammasome activation and protects rats from spinal cord injury-induced acute lung injury. Spinal Cord. 2016;54(11):951-956.

[125] Vohra P, Hoeppner L, Sagar G, et al. Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2012;302(2):L185-L192.

[126] Barreto T, Costola-de-Souza C, Margatho R, et al. Repeated Domperidone treatment modulates pulmonary cytokines in LPS-induced acute lung injury in mice. Int Immunopharmacol. 2018;56:43-50.

[127] Arruda J, Rocha N, Santos E, et al. Physalin pool from Physalis angulata L. leaves and physalin D inhibit P2×7 receptor function in vitro and acute lung injury in vivo. Biomed Pharmacother. 2021;142:112006.

[128] Liverani E, Rico M, Tsygankov A, Kilpatrick L, Kunapuli S. P2Y12 receptor modulates sepsis-induced inflammation. Arterioscler Thromb Vasc Biol. 2016;36(5):961-971.

[129] Ko I, Hwang J, Chang B, et al. Polydeoxyribonucleotide ameliorates lipopolysaccharide-induced acute lung injury via modulation of the MAPK/NF-κB signaling pathway in rats. Int Immunopharmacol. 2020;83:106444.

[130] Aggarwal N, D’Alessio F, Eto Y, et al. Macrophage A2A adenosinergic receptor modulates oxygen-induced augmentation of murine lung injury. Am J Respir Cell Mol Biol. 2013;48(5):635-646.

[131] Ribeiro A, Ferraz-de-Paula V, Pinheiro M, et al. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor. Eur J Pharmacol. 2012;678:78-85.

[132] He X, Hu J, Li J, et al. A feedback loop in PPARγ-adenosine A2A receptor signaling inhibits inflammation and attenuates lung damages in a mouse model of LPS-induced acute lung injury. Cell Signalling. 2013;25(9):1913-1923.

[133] Dai S, Wang H, Yang N, et al. Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury. J Exp Med. 2013;210(4):839-851.

[134] Bai W, Li P, Ning Y, et al. Reduction in blood glutamate levels combined with the genetic inactivation of A2AR significantly alleviate traumatic brain injury-induced acute lung injury. Shock. 2019;51(4):502-510.

[135] Li H, Liang X, Wu J, Yuan Y, Gao Y, Cai S. Simvastatin attenuates acute lung injury by activation of A2B adenosine receptor. Toxicol Appl Pharmacol. 2021;422:115460.

[136] Konrad F, Witte E, Vollmer I, Stark S, Reutershan J. Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium. Am J Physiol Lung Cell Mol Physiol. 2012;303(5):L425-L438.

[137] Schingnitz U, Hartmann K, Macmanus C, et al. Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol. 2010;184(9):5271-5279.

[138] Koscsó B, Trepakov A, Csóka B, et al. Stimulation of A2B adenosine receptors protects against trauma-hemorrhagic shock-induced lung injury. Purinergic Signal. 2013;9(3):427-432.

[139] He J, Zhao Y, Deng W, Wang D. Netrin-1 promotes epithelial sodium channel-mediated alveolar fluid clearance via activation of the adenosine 2B receptor in lipopolysaccharide-induced acute lung injury. Respiration. 2014;87(5):394-407.

[140] Csóka B, Németh Z, Rosenberger P, et al. A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. J Immunol. 2010;185(1):542-550.

[141] Gonzales J, Gorshkov B, Varn M, et al. Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2014;306(6):L497-L507.

[142] Duan J, Zhou Y, Zhou A, et al. Calcitonin gene-related peptide exerts anti-inflammatory property through regulating murine macrophages polarization in vitro. Mol Immunol. 2017;91:105-113.

[143] Karkischenko V, Skvortsova V, Gasanov M, et al. Inhaled [D-Ala]-dynorphin 1–6 prevents hyperacetylation and release of high mobility group box 1 in a mouse model of acute lung injury. J Immunol Res. 2021;2021:4414544.

[144] Nasseri S, Gurusamy M, Jung B, et al. Kinin B1 receptor antagonist BI113823 reduces acute lung injury. Crit Care Med. 2015;43(11):e499-e507.

[145] Campanholle G, Landgraf R, Borducchi E, et al. Bradykinin inducible receptor is essential to lipopolysaccharide-induced acute lung injury in mice. Eur J Pharmacol. 2010;634:132-137.

[146] Deng J, Wang D, Deng W, Li C, Tong J. The effect of endogenous angiotensin II on alveolar fluid clearance in rats with acute lung injury. Can Respir J. 2012;19(5):311-318.

[147] Han C, Zhang P, Liu Y, et al. Changes in angiotensin II and angiotensin-converting enzyme of different tissues after prolonged hyperoxia exposure. Undersea Hyperb Med. 2017;44(1):39-44.

[148] Xu J, Yang J, Chen J, Luo Q, Zhang Q, Zhang H. Vitamin D alleviates lipopolysaccharide induced acute lung injury via regulation of the renin angiotensin system. Mol Med Rep. 2017;16(5):7432-7438.

[149] Wu Z, Hu Z, Cai X, et al. Interleukin 22 attenuated angiotensin II induced acute lung injury through inhibiting the apoptosis of pulmonary microvascular endothelial cells. Sci Rep. 2017;7(1):2210.

[150] Chen Q, Yang Y, Huang Y, Pan C, Liu L, Qiu H. Angiotensin-(1-7) attenuates lung fibrosis by way of Mas receptor in acute lung injury. J Surg Res. 2013;185(2):740-747.

[151] Liu L, Qiu H, Yang Y, Wang L, Ding H, Li H. Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat. Arch Biochem Biophys. 2009;481(1):131-136.

[152] Wu Y, Yang X, Ju Y, Zhao F. Fraxinol attenuates LPS-induced acute lung injury by equilibrating ACE-Ang II-AT1R and ACE2-Ang (1-7)-Mas and inhibiting NLRP3. Pharm Biol. 2022;60(1):979-989.

[153] Chen L, Gong P, Su Y, et al. Angiotensin II type 2 receptor agonist attenuates LPS-induced acute lung injury through modulating THP-1-derived macrophage reprogramming. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(1):99-108.

[154] Chen Q, Kuang X, Yuan Q, et al. Lipoxin A attenuates LPS-induced acute lung injury via activation of the ACE2-Ang-(1-7)-Mas axis. Innate Immun. 2018;24(5):285-296.

[155] Klein N, Gembardt F, Supé S, et al. Angiotensin-(1-7) protects from experimental acute lung injury. Crit Care Med. 2013;41(11):e334-e343.

[156] Supé S, Kohse F, Gembardt F, Kuebler W, Walther T. Therapeutic time window for angiotensin-(1-7) in acute lung injury. Br J Pharmacol. 2016;173(10):1618-1628.

[157] Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005;11(8):875-879.

[158] Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112-116.

[159] Zhang L, Zhang Y, Qin X, et al. Recombinant ACE2 protein protects against acute lung injury induced by SARS-CoV-2 spike RBD protein. Crit Care. 2022;26(1):171.

[160] Minato T, Yamaguchi T, Hoshizaki M, et al. ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury. PLoS One. 2022;17(7):e0270920.

[161] Yamaguchi T, Hoshizaki M, Minato T, et al. ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury. Nat Commun. 2021;12(1):6791.

[162] Huang H, Wang J, Liu Z, Gao F. The angiotensin-converting enzyme 2/angiotensin (1-7)/mas axis protects against pyroptosis in LPS-induced lung injury by inhibiting NLRP3 activation. Arch Biochem Biophys. 2020;693:108562.

[163] Wang Y, Wu H, Niu W, et al. Tanshinone IIA attenuates paraquat induced acute lung injury by modulating angiotensin converting enzyme 2/angiotensin (1 7) in rats. Mol Med Rep. 2018;18(3):2955-2962.

[164] Chen Q, Liu J, Wang W, et al. Sini decoction ameliorates sepsis-induced acute lung injury via regulating ACE2-Ang (1-7)-Mas axis and inhibiting the MAPK signaling pathway. Biomed Pharmacother. 2019;115:108971.

[165] Liu J, Chen Q, Liu S, Yang X, Zhang Y, Huang F. Sini decoction alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis. Life Sci. 2018;208:139-148.

[166] Shi Y, Zhang B, Chen X, et al. Osthole protects lipopolysaccharide-induced acute lung injury in mice by preventing down-regulation of angiotensin-converting enzyme 2. Eur J Pharm Sci. 2013;48:819-824.

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