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Journal of Occupational Medicine and Toxicology
Published in: Journal of Occupational Medicine and Toxicology 1/2020

Open Access 01-12-2020 | Acute Respiratory Distress-Syndrome | Research

Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

Authors: Yanlin Zhang, Jian Zhao, Li Guan, Lijun Mao, Shuqiang Li, Jinyuan Zhao

Published in: Journal of Occupational Medicine and Toxicology | Issue 1/2020

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Abstract

Background

Chlorine gas (Cl2) exposure remains a public health concern in household, occupational, and transportation accidents around the world. The death rate associated with acute respiratory distress syndrome (ARDS) caused by high concentrations of Cl2 is very high, mainly because the pathogenesis of ARDS remains unclear. Histone H4 has been identified as an important endogenous pro-inflammatory molecule. The present study aimed to examine the pathogenic role of histone H4 in Cl2-induced ARDS.

Methods

ARDS was induced by Cl2 exposure in male C57BL/6 mice. Circulating histone H4, blood gas, pulmonary edema, endothelial activation, and neutrophil infiltration were measured during acute lung injury (ALI). Histone H4 or anti-H4 antibody was administered through the tail vein 1 h prior to Cl2 exposure to study the pathogenic role of histone H4. Toll-like receptor 2 knock-out (Tlr2-KO) and Tlr4-KO mice were used in conjunction with blocking antibody against TLR1, TLR2, TLR4, or TLR6 to explore the mechanism involved in histone H4-mediated injury.

Results

Cl2 exposure induced a concentration-dependent ALI. The levels of circulating histone H4 were positively correlated with Cl2 concentrations. Pretreatment with intravenous histone H4 further aggravated lethality rate, blood gas, endothelial activation, and neutrophil infiltration, while anti-H4 antibody showed protective effects. Tlr4 deficiency improved lethality rate, blood gas, and pulmonary edema, and prevented endothelial and neutrophil activation caused by Cl2 exposure. More importantly, Tlr4 gene deletion greatly diminished the effect of histone H4 or anti-H4 antibody observed in wild-type (WT) mice. The impact of Tlr2 on inflammatory injury was not significant. The role of TLRs was also validated by endothelial activation mediated by histone H4 in vitro.

Conclusions

Circulating histone H4 played a pro-inflammatory role in ARDS caused by Cl2. TLR4 was closely involved in histone H4-mediated inflammatory injury. Therefore, intervention targeting histone H4 is potentially protective.
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Literature
1.
Zellner T, Eyer F. Choking agents and chlorine gas-history, pathophysiology, clinical effects and treatment. Toxicol Lett. 2020;320:73–9.PubMedCrossRef
2.
3.
Van Sickle D, Wenck MA, Belflower A, Drociuk D, Ferdinands J, Holguin F, et al. Acute health effects after exposure to chlorine gas released after a train derailment. Am J Emerg Med. 2009;27(1):1–7.PubMedPubMedCentralCrossRef
4.
5.
Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–33.
6.
Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA. 2018;319(7):698–710.PubMedCrossRef
7.
8.
White CW, Martin JG. Chlorine gas inhalation: human clinical evidence of toxicity and experience in animal models. Proc Am Thorac Soc. 2010;7(4):257–63.PubMedPubMedCentralCrossRef
9.
Govier P, Coulson JM. Civilian exposure to chlorine gas: a systematic review. Toxicol Lett. 2018;293:249–52.PubMedCrossRef
10.
Kawai C, Kotani H, Miyao M, Ishida T, Jemail L, Abiru H, et al. Circulating extracellular histones are clinically relevant mediators of multiple organ injury. Am J Pathol. 2016;186(4):829–43.PubMedCrossRef
11.
Abrams ST, Zhang N, Manson J, Liu T, Dart C, Baluwa F, et al. Circulating histones are mediators of trauma associated lung injury. Am J Respir Crit Care Med. 2013;187(2):160–9.PubMedPubMedCentralCrossRef
12.
Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318–21.PubMedPubMedCentralCrossRef
13.
Allam R, Scherbaum CR, Darisipudi MN, Mulay SR, Hägele H, Lichtnekert J, et al. Histones from dying renal cells aggravate kidney injury via TlR2 and TlR4. J Am Soc Nephrol. 2012;23(8):1375–88.PubMedPubMedCentralCrossRef
14.
Monestier M, Fasy TM, Losman MJ, Novick KE, Muller S. Structure and binding properties of monoclonal antibodies to core histones from autoimmune mice. Mol Immunol. 1993;30(12):1069–75.PubMedCrossRef
15.
Kiani S, Chavez A, Tuttle M, Hall RN, Chari R, Ter-Ovanesyan D, et al. Cas9 gRNA engineering for genome editing, activation and repression. Nat Methods. 2015;12(11):1051–4.PubMedPubMedCentralCrossRef
16.
Zarogiannis SG, Jurkuvenaite A, Fernandez S, Doran SF, Yadav AK, Squadrito GL, et al. Ascorbate and deferoxamine administration after chlorine exposure decrease mortality and lung injury in mice. Am J Respir Cell Mol Biol. 2011;45(2):386–92.PubMedCrossRef
17.
18.
Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol. 2005;33(4):319–27.PubMedPubMedCentralCrossRef
19.
Cheng Z, Abrams ST, Alhamdi Y, Toh J, Yu W, Wang G, et al. Circulating histones are major mediators of multiple organ dysfunction syndrome in acute critical illnesses. Crit Care Med. 2019;47(8):e677–84.PubMedCrossRef
20.
Patel S. Danger-associated molecular patterns (DAMPs): the derivatives and triggers of inflammation. Curr Allergy Asthma Rep. 2018;18(11):63.PubMedCrossRef
21.
Magna M, Pisetsky DS. The alarmin properties of DNA and DNA-associated nuclear proteins. Clin Ther. 2016;38(5):1029–41.PubMedCrossRef
22.
23.
Grailer JJ, Ward PA. Lung inflammation and damage induced by extracellular histones. Inflamm Cell Signal. 2014;1(4):e131.PubMedPubMedCentral
24.
Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, et al. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB J. 2013;27(12):5010–21.PubMedPubMedCentralCrossRef
25.
Abrams ST, Zhang N, Dart C, Wang SS, Thachil J, Guan Y, et al. Human CRP defends against the toxicity of circulating histones. J Immunol. 2013;191(5):2495–502.PubMedCrossRef
26.
Gauthier VJ, Tyler LN, Mannik M. Blood clearance kinetics and liver uptake of mononucleosomes in mice. J Immunol. 1996;156(3):1151–6.PubMed
27.
Zhang Y, Wen Z, Guan L, Jiang P, Gu T, Zhao J, et al. Extracellular histones play an inflammatory role in acid aspiration-induced acute respiratory distress syndrome. Anesthesiology. 2015;122(1):127–39.PubMedCrossRef
28.
Huang H, Chen HW, Evankovich J, Yan W, Rosborough BR, Nace GW, et al. Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury. J Immunol. 2013;191(5):2665–79.PubMedCrossRef
29.
Kumar SV, Kulkarni OP, Mulay SR, Darisipudi MN, Romoli S, Thomasova D, et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol. 2015;26(10):2399–413.PubMedPubMedCentralCrossRef
30.
Shah M, Yellon DM, Davidson SM. The role of extracellular DNA and histones in ischaemia-reperfusion injury of the myocardium. Cardiovasc Drugs Ther. 2020;34(1):123–31.PubMedPubMedCentralCrossRef
31.
De Meyer SF, Suidan GL, Fuchs TA, Monestier M, Wagner DD. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler Thromb Vasc Biol. 2012;32(8):1884–91.PubMedPubMedCentralCrossRef
32.
Nakahara M, Ito T, Kawahara K, Yamamoto M, Nagasato T, Shrestha B, et al. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. PLoS One. 2013;8(9):e75961.PubMedPubMedCentralCrossRef
33.
Amoura Z, Piette JC, Chabre H, Cacoub P, Papo T, Wechsler B, et al. Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus: correlation with serum antinucleosome antibody titers and absence of clear association with disease activity. Arthritis Rheum. 1997;40(12):2217–25.PubMedCrossRef
34.
Shin SH, Joo HW, Kim MK, Kim JC, Sung YK. Extracellular histones inhibit hair shaft elongation in cultured human hair follicles and promote regression of hair follicles in mice. Exp Dermatol. 2012;21(12):956–8.PubMedCrossRef
35.
Chen R, Xie Y, Zhong X, Fu Y, Huang Y, Zhen Y, et al. Novel chemokine-like activities of histones in tumor metastasis. Oncotarget. 2016;7(38):61728–40.PubMedPubMedCentralCrossRef
36.
Westman J, Papareddy P, Dahlgren MW, Chakrakodi B, Norrby-Teglund A, Smeds E, et al. Extracellular histones induce chemokine production in whole blood ex vivo and leukocyte recruitment in vivo. PLoS Pathog. 2015;11(12):e1005319.PubMedPubMedCentralCrossRef
37.
38.
van Hinsbergh VW. Endothelium-role in regulation of coagulation and inflammation. Semin Immunopathol. 2012;34(1):93–106.PubMedCrossRef
39.
Wang HB, Wang JT, Zhang L, Geng ZH, Xu WL, Xu T, et al. P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol. 2007;8(8):882–92.PubMedCrossRef
40.
Jin H, Gebska MA, Blokhin IO, Wilson KM, Ketsawatsomkron P, Chauhan AK, et al. Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol. 2015;35(4):838–44.PubMedPubMedCentralCrossRef
41.
Ochoa CD, Wu S, Stevens T. New developments in lung endothelial heterogeneity: Von Willebrand factor, P-selectin, and the Weibel-Palade body. Semin Thromb Hemost. 2010;36(3):301–8.PubMedPubMedCentralCrossRef
42.
Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2007;35(8):1821–8.PubMedPubMedCentral
43.
44.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.PubMedCrossRef
45.
46.
Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187(5):2626–31.PubMedCrossRef
47.
Huang H, Evankovich J, Yan W, Nace G, Zhang L, Ross M, et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9 in mice. Hepatology. 2011;54(3):999–1008.PubMedCrossRef
48.
Furnrohr BG, Groer GJ, Sehnert B, Herrmann M, Voll RE. Interaction of histones with phospholipids–implications for the exposure of histones on apoptotic cells. Autoimmunity. 2007;40(4):322–6.PubMedCrossRef
49.
Kleine TJ, Lewis PN, Lewis SA. Histone-induced damage of a mammalian epithelium: the role of protein and membrane structure. Am J Phys. 1997;273(6):C1925–36.CrossRef
50.
Silvestre-Roig C, Braster Q, Wichapong K, Lee EY, Teulon JM, Berrebeh N, et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature. 2019;569(7755):236–40.PubMedPubMedCentralCrossRef
51.
Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389(6649):349–52.PubMedCrossRef
52.
Koprinarova M, Schnekenburger M, Diederich M. Role of histone acetylation in cell cycle regulation. Curr Top Med Chem. 2016;16(7):732–44.PubMedCrossRef
53.
Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178–85.PubMedCrossRef
54.
Szatmary P, Huang W, Criddle D, Tepikin A, Sutton R. Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders. J Cell Mol Med. 2018;22(10):4617–29.PubMedPubMedCentralCrossRef
55.
Alhamdi Y, Abrams ST, Cheng Z, Jing S, Su D, Liu Z, et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10):2094–103.PubMedCrossRef
56.
Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, Monestier M, et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122(7):2661–71.PubMedPubMedCentralCrossRef
57.
Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62(2):600–14.PubMedCrossRef
58.
Merza M, Rahman M, Zhang S, Hwaiz R, Regner S, Schmidtchen A, et al. Human thrombin-derived host defense peptides inhibit neutrophil recruitment and tissue injury in severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014;307(9):G914–21.PubMedCrossRef
59.
Alcantara FF, Iglehart DJ, Ochs RL. Heparin in plasma samples causes nonspecific binding to histones on Western blots. J Immunol Methods. 1999;226(1–2):11–8.PubMedCrossRef
60.
Wang F, Zhang N, Li B, Liu L, Ding L, Wang Y, et al. Heparin defends against the toxicity of circulating histones in sepsis. Front Biosci (Landmark Ed). 2015;20:1259–70.CrossRef
61.
Lam FW, Cruz MA, Leung HC, Parikh KS, Smith CW, Rumbaut RE. Histone induced platelet aggregation is inhibited by normal albumin. Thromb Res. 2013;132(1):69–76.PubMedCrossRef
62.
Gamberucci A, Fulceri R, Marcolongo P, Pralong WF, Benedetti A. Histones and basic polypeptides activate Ca2+/cation influx in various cell types. Biochem J. 1998;331(Pt2):623–30.PubMedPubMedCentralCrossRef
63.
Merza M, Hartman H, Rahman M, Hwaiz R, Zhang E, Renström E, et al. Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology. 2015;149(7):1920–31.PubMedCrossRef
64.
Metadata
Title
Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome
Authors
Yanlin Zhang
Jian Zhao
Li Guan
Lijun Mao
Shuqiang Li
Jinyuan Zhao
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Occupational Medicine and Toxicology / Issue 1/2020
Electronic ISSN: 1745-6673
DOI
https://doi.org/10.1186/s12995-020-00282-z

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