Targeting Notch-activated M1 macrophages attenuate lung tissue damage in a rat model of ventilator induced lung injury

Yin,Danping; Wang,Weiming; Han,Wei; Fan,Chen

doi:10.3892/ijmm.2019.4315

Targeting Notch-activated M1 macrophages attenuate lung tissue damage in a rat model of ventilator induced lung injury

Authors:
- Danping Yin
- Weiming Wang
- Wei Han
- Chen Fan
View Affiliations

Affiliations: Department of Disease Prevention and Control, No. 960 Hospital of PLA, Jinan, Shandong 250031, P.R. China, Electrocardiogram Room, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264001, P.R. China, Department of Training, No. 960 Hospital of PLA, Jinan, Shandong 250031, P.R. China, Department of Laboratory Diagnosis, No. 960 Hospital of PLA, Jinan, Shandong 250031, P.R. China
Published online on: August 16, 2019 https://doi.org/10.3892/ijmm.2019.4315
Pages: 1388-1398
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ventilator induced lung injury (VILI) may be involved in the activation of alveolar macrophages. The purpose of this study was to investigate the relationship between the Notch signaling pathway and macrophage polarization in VILI. The VILI model was established using rats. Hematoxylin‑eosin staining was used to test the lung tissue morphology. Bicinchoninic acid assay and ELISA were performed to detect protein and tumor necrosis factor (TNF)‑α, interleukin (IL)‑6, IL‑10 levels in bronchoalveolar lavage fluids (BALF), respectively. The ratio of alveolar M1 and M2 macrophages was detected by flow cytometry. The mRNA and protein expression levels of Notch pathway‑related proteins were determined using reverse transcription‑quantitative PCR and western blotting. The present study found that high‑frequency mechanical ventilation could cause pulmonary edema and increase the levels of protein, TNF‑α and IL‑6 in BALF while decreasing the level of IL‑10 in BALF. High‑frequency mechanical ventilation also induced polarization of alveolar macrophages to M1. The results also showed a significant increase in the levels of Notch pathway‑related proteins including notch intracellular domain, Hes1, Hes5 and Hey1. Injection of N‑[N‑(3,5‑difluorophenylacetyl)‑1‑alanyl] phenylglycine t‑butyl ester could inhibit the Notch pathway and such an inhibition protected lung tissue and reduced lung inflammation caused by mechanical ventilation. After the Notch pathway was inhibited, the level of M1 polarization of macrophages caused by high‑frequency mechanical ventilation was reduced. VILI caused pulmonary inflammation and macrophages to polarize to M1 and upregulated the expression levels of Notch pathway‑related proteins. The inhibition of Notch pathway also reduced the proportion of M1 macrophages and inflammatory responses.

View Figures

View References

1	Sutherasan Y, Vargas M and Pelosi P: Protective mechanical ventilation in the non-injured lung: Review and meta-analysis. Crit Care. 18:2112014. View Article : Google Scholar : PubMed/NCBI
2	Schnell D, Timsit JF, Darmon M, Vesin A, Goldgran-Toledano D, Dumenil AS, Garrouste-Orgeas M, Adrie C, Bouadma L, Planquette B, et al: Noninvasive mechanical ventilation in acute respiratory failure: Trends in use and outcomes. Intensive Care Med. 40:582–591. 2014. View Article : Google Scholar : PubMed/NCBI
3	Unroe M, Kahn JM, Carson SS, Govert JA, Martinu T, Sathy SJ, Clay AS, Chia J, Gray A, Tulsky JA and Cox CE: One-year trajectories of care and resource utilization for recipients of prolonged mechanical ventilation: A cohort study. Ann Intern Med. 153:167–175. 2010. View Article : Google Scholar : PubMed/NCBI
4	Müller-Redetzky HC, Felten M, Hellwig K, Wienhold SM, Naujoks J, Opitz B, Kershaw O, Gruber AD, Suttorp N and Witzenrath M: Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice. Crit Care. 19:232015. View Article : Google Scholar : PubMed/NCBI
5	Hamlington KL, Smith BJ, Allen GB and Bates JH: Predicting ventilator-induced lung injury using a lung injury cost function. J Appl Physiol 1985. 121:106–114. 2016. View Article : Google Scholar : PubMed/NCBI
6	Reddy SP, Hassoun PM and Brower R: Redox imbalance and ventilator-induced lung injury. Antioxid Redox Signal. 9:2003–2012. 2007. View Article : Google Scholar : PubMed/NCBI
7	Curley GF, Contreras M, Higgins B, O'Kane C, McAuley DF, O'Toole D and Laffey JG: Evolution of the inflammatory and fibroproliferative responses during resolution and repair after ventilator-induced lung injury in the rat. Anesthesiology. 115:1022–1032. 2011. View Article : Google Scholar : PubMed/NCBI
8	Bertok S, Wilson MR, Morley PJ, de Wildt R, Bayliffe A and Takata M: Selective inhibition of intra-alveolar p55 TNF receptor attenuates ventilator-induced lung injury. Thorax. 67:244–251. 2012. View Article : Google Scholar :
9	Wilson MR, Wakabayashi K, Bertok S, Oakley CM, Patel BV, O'Dea KP, Cordy JC, Morley PJ, Bayliffe AI and Takata M: Inhibition of TNF receptor p55 By a domain antibody attenuates the initial phase of acid-induced lung injury in mice. Front Immunol. 8:1282017. View Article : Google Scholar : PubMed/NCBI
10	Opitz B, van Laak V, Eitel J and Suttorp N: Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med. 181:1294–1309. 2010. View Article : Google Scholar : PubMed/NCBI
11	Martinez FO and Gordon S: The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000 Prime Rep. 6:132014. View Article : Google Scholar
12	Jablonski KA, Amici SA, Webb LM, Ruiz-Rosado Jde D, Popovich PG, Partida-Sanchez S and Guerau-de-Arellano M: Novel markers to delineate murine M1 and M2 macrophages. PLoS One. 10:e01453422015. View Article : Google Scholar : PubMed/NCBI
13	Wynn TA, Chawla A and Pollard JW: Macrophage biology in development, homeostasis and disease. Nature. 496:445–455. 2013. View Article : Google Scholar : PubMed/NCBI
14	Jaecklin T, Otulakowski G and Kavanagh BP: Do soluble mediators cause ventilator-induced lung injury and multi-organ failure? Intensive Care Med. 36:750–757. 2010. View Article : Google Scholar : PubMed/NCBI
15	Dai H, Pan L, Lin F, Ge W, Li W and He S: Mechanical ventilation modulates Toll-like receptors 2, 4, and 9 on alveolar macrophages in a ventilator-induced lung injury model. J Thorac Dis. 7:616–624. 2015.PubMed/NCBI
16	Kopan R and Ilagan MX: The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell. 137:216–233. 2009. View Article : Google Scholar : PubMed/NCBI
17	Yang Z, Guo L, Liu D, Sun L, Chen H, Deng Q, Liu Y, Yu M, Ma Y, Guo N and Shi M: Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 6:5072–5087. 2015.PubMed/NCBI
18	Han H, Gong G, Bai X, Lin YC, Sun J, Wang W, Zhao Y, Yang L, Wang X, Zhang Z, et al: Inhibition of Notch signaling protects mouse lung against zymosan-induced injury. Shock. 40:312–319. 2013. View Article : Google Scholar : PubMed/NCBI
19	Tsao PN, Wei SC, Huang MT, Lee MC, Chou HC, Chen CY and Hsieh WS: Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response. J Biomed Sci. 18:562011. View Article : Google Scholar : PubMed/NCBI
20	Jiao Z, Wang W, Hua S, Liu M, Wang H, Wang X, Chen Y, Xu H and Lu L: Blockade of Notch signaling ameliorates murine collagen-induced arthritis via suppressing Th1 and Th17 cell responses. Am J Pathol. 184:1085–1093. 2014. View Article : Google Scholar : PubMed/NCBI
21	Park JS, Kim SH, Kim K, Jin CH, Choi KY, Jang J, Choi Y, Gwon AR, Baik SH, Yun UJ, et al: Inhibition of Notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis. 74:267–274. 2015. View Article : Google Scholar
22	Huang C, Pan L, Lin F, Dai H and Fu R: Monoclonal antibody against Toll-like receptor 4 attenuates ventilator-induced lung injury in rats by inhibiting MyD88- and NF-κB-dependent signaling. Int J Mol Med. 39:693–700. 2017. View Article : Google Scholar : PubMed/NCBI
23	Whitehead TC, Zhang H, Mullen B and Slutsky AS: Effect of mechanical ventilation on cytokine response to intratracheal lipopolysaccharide. Anesthesiology. 101:52–58. 2004. View Article : Google Scholar : PubMed/NCBI
24	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
25	Silva PL, Negrini D and Rocco PR: Mechanisms of ventilator-induced lung injury in healthy lungs. Best Pract Res Clin Anaesthesiol. 29:301–313. 2015. View Article : Google Scholar : PubMed/NCBI
26	Cressoni M, Gotti M, Chiurazzi C, Massari D, Algieri I, Amini M, Cammaroto A, Brioni M, Montaruli C, Nikolla K, et al: Mechanical power and development of Ventilator-induced lung injury. Anesthesiology. 124:1100–1108. 2016. View Article : Google Scholar : PubMed/NCBI
27	Borges JB, Costa EL, Suarez-Sipmann F, Widström C, Larsson A, Amato M and Hedenstierna G: Early inflammation mainly affects normally and poorly aerated lung in experimental ventilator-induced lung injury*. Crit Care Med. 42:e279–e287. 2014. View Article : Google Scholar : PubMed/NCBI
28	Xu YH and Guo NL: USP14 inhibitor IU1 prevents ventilator-induced lung injury in rats. Cell Mol Biol (Noisy-le-grand). 60:50–54. 2014.
29	Malaviya R, Sunil VR, Venosa A, Verissimo VL, Cervelli JA, Vayas KN, Hall L, Laskin JD and Laskin DL: Attenuation of nitrogen mustard-induced pulmonary injury and fibrosis by anti-tumor necrosis factor-α antibody. Toxicol Sci. 148:71–88. 2015. View Article : Google Scholar : PubMed/NCBI
30	Halbertsma FJ, Vaneker M, Scheffer GJ and van der Hoeven JG: Cytokines and biotrauma in ventilator-induced lung injury: A critical review of the literature. Neth J Med. 63:382–392. 2005.PubMed/NCBI
31	Ko YA, Yang MC, Huang HT, Hsu CM and Chen LW: NF-κB activation in myeloid cells mediates ventilator-induced lung injury. Respir Res. 14:692013. View Article : Google Scholar
32	Huang C, Pan L, Lin F, Qian W and Li W: Alveolar macrophage TLR4/MyD88 signaling pathway contributes to ventilator-induced lung injury in rats. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 31:182–185. 1892015.In Chinese.
33	Morimoto M, Nishinakamura R, Saga Y and Kopan R: Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development. 139:4365–4373. 2012. View Article : Google Scholar : PubMed/NCBI
34	Nagase H and Nakayama K: γ-Secretase-regulated signaling typified by Notch signaling in the immune system. Curr Stem Cell Res Ther. 8:341–356. 2013. View Article : Google Scholar : PubMed/NCBI
35	Katoh M and Katoh M: Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Int J Oncol. 31:461–466. 2007.PubMed/NCBI
36	Ma Y, Bian J and Zhang F: Inhibition of perillyl alcohol on cell invasion and migration depends on the Notch signaling pathway in hepatoma cells. Mol Cell Biochem. 411:307–315. 2016. View Article : Google Scholar
37	Liu X, Cong N, Cheng X, Ma R, Wang J, Huang YB, Zhao M, Wang XW, Chi FL and Ren DD: The role of the Notch signal pathway in mucosal cell metaplasia in mouse acute otitis media. Sci Rep. 7:45882017. View Article : Google Scholar : PubMed/NCBI
38	Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, Hu XB, Zheng MH, Liang L, Feng L, et al: Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70:4840–4849. 2010. View Article : Google Scholar : PubMed/NCBI
39	Sun W, Zhang H, Wang H, Chiu YG, Wang M, Ritchlin CT, Kiernan A, Boyce BF and Xing L: Targeting notch-activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis. J Bone Miner Res. 32:1469–1480. 2017. View Article : Google Scholar : PubMed/NCBI
40	Huang F, Zhao JL, Wang L, Gao CC, Liang SQ, An DJ, Bai J, Chen Y, Han H and Qin HY: miR-148a-3p mediates Notch signaling to promote the differentiation and M1 activation of macrophages. Front Immunol. 8:13272017. View Article : Google Scholar : PubMed/NCBI
41	Wongchana W and Palaga T: Direct regulation of interleukin-6 expression by Notch signaling in macrophages. Cell Mol Immunol. 9:155–162. 2012. View Article : Google Scholar
42	Zhang H, Hilton MJ, Anolik JH, Welle SL, Zhao C, Yao Z, Li X, Wang Z, Boyce BF and Xing L: NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB. J Clin Invest. 124:3200–3214. 2014. View Article : Google Scholar : PubMed/NCBI
43	Ortiz-Masia D, Cosin-Roger J, Calatayud S, Hernández C, Alós R, Hinojosa J, Esplugues JV and Barrachina MD: M1 macrophages activate Notch signalling in epithelial cells: Relevance in crohn's disease. J Crohns Colitis. 10:582–592. 2016. View Article : Google Scholar : PubMed/NCBI
44	Zhao JL, Huang F, He F, Gao CC, Liang SQ, Ma PF, Dong GY, Han H and Qin HY: Forced activation of Notch in macrophages represses tumor growth by upregulating miR-125a and disabling tumor-associated macrophages. Cancer Res. 76:1403–1415. 2016. View Article : Google Scholar : PubMed/NCBI