Mitochondrial alarmins are tissue mediators of ventilator-induced lung injury and ARDS


Autoři: Serge Grazioli aff001;  Irène Dunn-Siegrist aff001;  Laure-Anne Pauchard aff003;  Mathieu Blot aff005;  Pierre-Emmanuel Charles aff003;  Jérôme Pugin aff001
Působiště autorů: Intensive Care Laboratory, Department of Microbiology and Molecular Medicine, University Hospitals of Geneva & Faculty of Medicine, Genève, Switzerland aff001;  Department of Pediatrics, Division of Neonatal and Pediatric Intensive Care, University Hospital of Geneva, Genève, Switzerland aff002;  Intensive Care Unit, University Hospital of Dijon, Dijon, France aff003;  U.M.R. 1231, I.N.S.E.R.M, Burgundy University, Dijon, France aff004;  Department of Infectious Diseases, University Hospital of Dijon, Dijon, France aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225468

Souhrn

Rationale

Endogenous tissue mediators inducing lung inflammation in the context of ventilator-induced lung injury (VILI) and acute respiratory distress syndrome (ARDS) are ill-defined.

Objectives

To test whether mitochondrial alarmins are released during VILI, and are associated with lung inflammation.

Methods

Release of mitochondrial DNA, adenosine triphosphate (ATP), and formyl-Met-Leu-Phe (fMLP) peptide-dependent neutrophil chemotaxis were measured in conditioned supernatants from human alveolar type II-like (A549) epithelial cells submitted to cyclic stretch in vitro. Similar measurements were performed in bronchoalveolar lavage fluids from rabbits submitted to an injurious ventilatory regimen, and from patients with ARDS.

Measurements and main results

Mitochondrial DNA was released by A549 cells during cell stretching, and was found elevated in BAL fluids from rabbits during VILI, and from ARDS patients. Cyclic stretch-induced interleukin-8 (IL-8) of A549 cells could be inhibited by Toll-like receptor 9 (TLR9) blockade. ATP concentrations were increased in conditioned supernatants from A549 cells, and in rabbit BAL fluids during VILI. Neutrophil chemotaxis induced by A549 cells conditioned supernatants was essentially dependent on fMLP rather than IL-8. A synergy between cyclic stretch-induced alarmins and lipopolysaccharide (LPS) was found in monocyte-derived macrophages in the production of IL-1ß.

Conclusions

Mitochondrial alarmins are released during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen, and found in BAL fluids from ARDS patients, particularly in those with high alveolar inflammation. These alarmins are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells.

Klíčová slova:

Acute respiratory distress syndrome – Chemotaxis – Inflammation – Macrophages – Mitochondria – Mitochondrial DNA – Neutrophils – Rabbits


Zdroje

1. Pugin J. Is the ventilator responsible for lung and systemic inflammation? Intensive Care Med. 2002;28(7):817–9. doi: 10.1007/s00134-002-1320-8 12349817.

2. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997;99(5):944–52. doi: 10.1172/JCI119259 9062352; PubMed Central PMCID: PMC507902.

3. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301–8. doi: 10.1056/NEJM200005043421801 10793162.

4. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308(16):1651–9. doi: 10.1001/jama.2012.13730 23093163.

5. Kawano T, Mori S, Cybulsky M, Burger R, Ballin A, Cutz E, et al. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol. 1987;62(1):27–33. doi: 10.1152/jappl.1987.62.1.27 3558186.

6. Pugin J, Ricou B, Steinberg KP, Suter PM, Martin TR. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am J Respir Crit Care Med. 1996;153(6 Pt 1):1850–6. doi: 10.1164/ajrccm.153.6.8665045 8665045.

7. Pugin J, Verghese G, Widmer MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med. 1999;27(2):304–12. doi: 10.1097/00003246-199902000-00036 10075054.

8. Dunn I, Pugin J. Mechanical ventilation of various human lung cells in vitro: identification of the macrophage as the main producer of inflammatory mediators. Chest. 1999;116(1 Suppl):95S–7S. doi: 10.1378/chest.116.suppl_1.95s 10424615.

9. Pugin J, Dunn I, Jolliet P, Tassaux D, Magnenat JL, Nicod LP, et al. Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol. 1998;275(6 Pt 1):L1040–50. doi: 10.1152/ajplung.1998.275.6.L1040 9843840.

10. Bregeon F, Roch A, Delpierre S, Ghigo E, Autillo-Touati A, Kajikawa O, et al. Conventional mechanical ventilation of healthy lungs induced pro-inflammatory cytokine gene transcription. Respir Physiol Neurobiol. 2002;132(2):191–203. doi: 10.1016/s1569-9048(02)00069-1 12161332.

11. Charles PE, Martin L, Etienne M, Croisier D, Piroth L, Lequeu C, et al. Influence of positive end-expiratory pressure (PEEP) on histopathological and bacteriological aspects of pneumonia during low tidal volume mechanical ventilation. Intensive Care Med. 2004;30(12):2263–70. doi: 10.1007/s00134-004-2442-y 15536527.

12. Vaneker M, Halbertsma FJ, van Egmond J, Netea MG, Dijkman HB, Snijdelaar DG, et al. Mechanical ventilation in healthy mice induces reversible pulmonary and systemic cytokine elevation with preserved alveolar integrity: an in vivo model using clinical relevant ventilation settings. Anesthesiology. 2007;107(3):419–26. doi: 10.1097/01.anes.0000278908.22686.01 17721244.

13. Oudin S, Pugin J. Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch. Am J Respir Cell Mol Biol. 2002;27(1):107–14. doi: 10.1165/ajrcmb.27.1.4766 12091253.

14. Stroetz RW, Vlahakis NE, Walters BJ, Schroeder MA, Hubmayr RD. Validation of a new live cell strain system: characterization of plasma membrane stress failure. J Appl Physiol. 2001;90(6):2361–70. doi: 10.1152/jappl.2001.90.6.2361 11356803.

15. Vlahakis NE, Hubmayr RD. Invited review: plasma membrane stress failure in alveolar epithelial cells. J Appl Physiol. 2000;89(6):2490–6;discussion 7. doi: 10.1152/jappl.2000.89.6.2490 11090606.

16. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330(6002):362–6. doi: 10.1126/science.1195491 20947763.

17. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7. doi: 10.1038/nature08780 20203610; PubMed Central PMCID: PMC2843437.

18. Grazioli S, Pugin J. Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front Immunol. 2018;9:832. doi: 10.3389/fimmu.2018.00832 29780380; PubMed Central PMCID: PMC5946030.

19. Kuipers MT, van der Poll T, Schultz MJ, Wieland CW. Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury. Crit Care. 2011;15(6):235. doi: 10.1186/cc10437 22216838; PubMed Central PMCID: PMC3388678.

20. Matsuyama H, Amaya F, Hashimoto S, Ueno H, Beppu S, Mizuta M, et al. Acute lung inflammation and ventilator-induced lung injury caused by ATP via the P2Y receptors: an experimental study. Respir Res. 2008;9:79. doi: 10.1186/1465-9921-9-79 19077288; PubMed Central PMCID: PMC2627837.

21. Pugin J. How tissue injury alarms the immune system and causes a systemic inflammatory response syndrome. Ann Intensive Care. 2012;2(1):27. doi: 10.1186/2110-5820-2-27 22788849; PubMed Central PMCID: PMC3488542.

22. Wu J, Yan Z, Schwartz DE, Yu J, Malik AB, Hu G. Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. J Immunol. 2013;190(7):3590–9. doi: 10.4049/jimmunol.1200860 23436933; PubMed Central PMCID: PMC3608749.

23. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26. doi: 10.1016/s1097-2765(02)00599-3 12191486.

24. Frank JA, Pittet JF, Wray C, Matthay MA. Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade. Thorax. 2008;63(2):147–53. doi: 10.1136/thx.2007.079608 17901159.

25. Charles PE, Tissieres P, Barbar SD, Croisier D, Dufour J, Dunn-Siegrist I, et al. Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide. Crit Care. 2011;15(4):R181. doi: 10.1186/cc10330 21794115; PubMed Central PMCID: PMC3387624.

26. Mortaz E, Adcock IM, Ito K, Kraneveld AD, Nijkamp FP, Folkerts G. Cigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptor. Eur Respir J. 2010;36(5):1143–54. doi: 10.1183/09031936.00062209 19840968.

27. Panigrahi S, Ma Y, Hong L, Gao D, West XZ, Salomon RG, et al. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res. 2013;112(1):103–12. doi: 10.1161/CIRCRESAHA.112.274241 23071157; PubMed Central PMCID: PMC3537845.

28. Drifte G, Dunn-Siegrist I, Tissieres P, Pugin J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med. 2013;41(3):820–32. doi: 10.1097/CCM.0b013e318274647d 23348516.

29. Park WY, Goodman RB, Steinberg KP, Ruzinski JT, Radella F 2nd, Park DR, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1896–903. doi: 10.1164/ajrccm.164.10.2104013 11734443.

30. Rich PB, Douillet CD, Mahler SA, Husain SA, Boucher RC. Adenosine triphosphate is released during injurious mechanical ventilation and contributes to lung edema. J Trauma. 2003;55(2):290–7. doi: 10.1097/01.TA.0000078882.11919.AF 12913640.

31. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–49. doi: 10.1056/NEJM200005043421806 10793167.

32. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999;282(1):54–61. doi: 10.1001/jama.282.1.54 10404912.

33. Tschopp J. Mitochondria: Sovereign of inflammation? Eur J Immunol. 2011;41(5):1196–202. doi: 10.1002/eji.201141436 21469137.

34. Zhang JZ, Liu Z, Liu J, Ren JX, Sun TS. Mitochondrial DNA induces inflammation and increases TLR9/NF-kappaB expression in lung tissue. Int J Mol Med. 2014;33(4):817–24. doi: 10.3892/ijmm.2014.1650 24535292.

35. McIlroy DJ, Jarnicki AG, Au GG, Lott N, Smith DW, Hansbro PM, et al. Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J Crit Care. 2014;29(6):1133 e1-5. doi: 10.1016/j.jcrc.2014.07.013 25128442.

36. McIlroy DJ, Bigland M, White AE, Hardy BM, Lott N, Smith DW, et al. Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery. J Trauma Acute Care Surg. 2015;78(2):282–8. doi: 10.1097/TA.0000000000000519 25602756; PubMed Central PMCID: PMC4323572.

37. Yao X, Carlson D, Sun Y, Ma L, Wolf SE, Minei JP, et al. Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model. PLoS One. 2015;10(10):e0139416. doi: 10.1371/journal.pone.0139416 26448624; PubMed Central PMCID: PMC4598156.

38. Unuma K, Aki T, Funakoshi T, Hashimoto K, Uemura K. Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells: Involvement of autophagy. Autophagy. 2015;11(9):1520–36. doi: 10.1080/15548627.2015.1063765 26102061; PubMed Central PMCID: PMC4590602.

39. McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 2014;33(4):282–95. doi: 10.1002/embj.201385902 24446486; PubMed Central PMCID: PMC3989637.

40. Ali MH, Pearlstein DP, Mathieu CE, Schumacker PT. Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2004;287(3):L486–96. doi: 10.1152/ajplung.00389.2003 15090367.

41. Davidson BA, Vethanayagam RR, Grimm MJ, Mullan BA, Raghavendran K, Blackwell TS, et al. NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury. J Immunol. 2013;190(4):1714–24. doi: 10.4049/jimmunol.1202410 23296708; PubMed Central PMCID: PMC3563868.

42. Lin JY, Jing R, Lin F, Ge WY, Dai HJ, Pan L. High Tidal Volume Induces Mitochondria Damage and Releases Mitochondrial DNA to Aggravate the Ventilator-Induced Lung Injury. Front Immunol. 2018;9:1477. doi: 10.3389/fimmu.2018.01477 30018615; PubMed Central PMCID: PMC6037891.

43. Timmermans K, Kox M, Vaneker M, Pickkers P, Scheffer GJ. Mitochondrial DNA and TLR9 Signaling Is Not Involved in Mechanical Ventilation-Induced Inflammation. Anesth Analg. 2017;124(2):531–4. doi: 10.1213/ANE.0000000000001554 28099322

44. Blot M, Pauchard LA, Dunn I, Donze J, Malnuit S, Rebaud C, et al. Mechanical ventilation and Streptococcus pneumoniae pneumonia alter mitochondrial homeostasis. Sci Rep. 2018;8(1):11718. doi: 10.1038/s41598-018-30226-x 30082877; PubMed Central PMCID: PMC6078986.

45. Haden DW, Suliman HB, Carraway MS, Welty-Wolf KE, Ali AS, Shitara H, et al. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med. 2007;176(8):768–77. doi: 10.1164/rccm.200701-161OC 17600279; PubMed Central PMCID: PMC2020830.

46. Hajizadeh S, DeGroot J, TeKoppele JM, Tarkowski A, Collins LV. Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis. Arthritis Res Ther. 2003;5(5):R234–40. doi: 10.1186/ar787 12932286; PubMed Central PMCID: PMC193725.

47. Sarma JV, Ward PA. Oxidants and redox signaling in acute lung injury. Compr Physiol. 2011;1(3):1365–81. doi: 10.1002/cphy.c100068 23733646.

48. Abraham E. Neutrophils and acute lung injury. Crit Care Med. 2003;31(4 Suppl):S195–9. doi: 10.1097/01.CCM.0000057843.47705.E8 12682440.

49. Crouser ED, Shao G, Julian MW, Macre JE, Shadel GS, Tridandapani S, et al. Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors. Crit Care Med. 2009;37(6):2000–9. doi: 10.1097/CCM.0b013e3181a001ae 19384205; PubMed Central PMCID: PMC2743203.

50. Narimanbekov IO, Rozycki HJ. Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model. Exp Lung Res. 1995;21(2):239–54. doi: 10.3109/01902149509068830 7774527.

51. Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev. 2011;243(1):136–51. doi: 10.1111/j.1600-065X.2011.01046.x 21884173.

52. Kuipers MT, Aslami H, Janczy JR, van der Sluijs KF, Vlaar AP, Wolthuis EK, et al. Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. Anesthesiology. 2012;116(5):1104–15. doi: 10.1097/ALN.0b013e3182518bc0 22531249

53. Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013;10(12):e1001577; discussion e. doi: 10.1371/journal.pmed.1001577 24391478; PubMed Central PMCID: PMC3876981.

54. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. doi: 10.1146/annurev.iy.12.040194.005015 8011301.

55. Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immunol. 2007;8(1):11–3. doi: 10.1038/ni0107-11 17179963.

56. Bregeon F, Delpierre S, Chetaille B, Kajikawa O, Martin TR, Autillo-Touati A, et al. Mechanical ventilation affects lung function and cytokine production in an experimental model of endotoxemia. Anesthesiology. 2005;102(2):331–9. doi: 10.1097/00000542-200502000-00015 15681948.


Článek vyšel v časopise

PLOS One


2019 Číslo 11