title: Chlorine gas exposure increases susceptibility to invasive lung fungal infection.
abstract: Chlorine (Cl₂) is a highly irritating and reactive gas with potential occupational and environmental hazards. Acute exposure to Cl₂ induces severe epithelial damage, airway hyperreactivity, impaired alveolar fluid clearance, and pulmonary edema in the presence of heightened inflammation and significant neutrophil accumulation in the lungs. Herein, we investigated whether Cl₂ exposure affected the lung antimicrobial immune response leading to increased susceptibility to opportunistic infections. Mice exposed to Cl₂ and challenged intratracheally 24 h thereafter with the opportunistic mold Aspergillus fumigatus demonstrated an >500-fold increase in A. fumigatus lung burden 72 h postchallenge compared with A. fumigatus mice exposed to room air. Cl₂-exposed A. fumigatus challenged mice also demonstrated significantly higher lung resistance following methacholine challenge and increased levels of plasma proteins (albumin and IgG) in the bronchoalveolar lavage fluid. Despite enhanced recruitment of inflammatory cells to the lungs of Cl₂-exposed A. fumigatus challenged mice, these cells (>60% of which were neutrophils) demonstrated a profound impairment in generating superoxide. Significantly higher A. fumigatus burden in the lungs of Cl₂ exposed mice correlated with enhanced production of IL-6, TNF-α, CXCL1, CCL2, and CCL3. Surprisingly, however, Cl₂-exposed A. fumigatus challenged mice had a specific impairment in the production of IL-17A and IL-22 in the lungs compared with mice exposed to room air and challenged with A. fumigatus. In summary, our results indicate that Cl₂ exposure markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.
authors.affiliation: Department of Medicine, Pulmonary Injury and Repair Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Gessner
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Doran
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yu
authors.forename: Chad W
authors.initials: CW
authors.lastname: Dunaway
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000209:etiology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002713:Chlorine / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000502:physiology; D008172:Lung Diseases, Fungal / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D013481:Superoxides / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D018925:Chemokines; D002713:Chlorine; D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D013481:Superoxides; D000097043:Interleukin-22
keywords: Aspergillus fumigatus; inflammation; lung injury; neutrophils
references.citation: J Occup Med. 1985 Jul;27(7):473-6
references.pmid: 4032082
references.citation: J Biol Chem. 1970 Aug 25;245(16):4053-7
references.pmid: 5496991
references.citation: Immunity. 2000 Nov;13(5):715-25
references.pmid: 11114383
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Mar;300(3):L362-9
references.pmid: 21148791
references.citation: J Immunol. 2011 Feb 1;186(3):1666-1674
references.pmid: 21178015
references.citation: J Immunol. 2009 Apr 15;182(8):4938-46
references.pmid: 19342673
references.citation: J Immunol. 2005 Jul 1;175(1):404-12
references.pmid: 15972674
references.citation: Immunity. 2004 Aug;21(2):241-54
references.pmid: 15308104
references.citation: J Biol Chem. 2001 Nov 23;276(47):43818-23
references.pmid: 11567029
references.citation: J Allergy Clin Immunol. 2011 May;127(5):1243-52.e7
references.pmid: 21376380
references.citation: Blood. 2003 Aug 1;102(3):827-33
references.pmid: 12689933
references.citation: BMC Immunol. 2012 Jul 09;13:38
references.pmid: 22776294
references.citation: Mucosal Immunol. 2013 Jan;6(1):69-82
references.pmid: 22739232
references.citation: J Infect Dis. 1997 Apr;175(4):1012-5
references.pmid: 9086172
references.citation: Int J Tuberc Lung Dis. 2009 Aug;13(8):936-44
references.pmid: 19723372
references.citation: J Immunol. 2011 Nov 15;187(10):5357-62
references.pmid: 21964025
references.citation: Inhal Toxicol. 2008 Jul;20(9):783-93
references.pmid: 18645717
references.citation: J Immunol. 1999 Dec 1;163(11):6086-94
references.pmid: 10570298
references.citation: Infect Immun. 2006 Dec;74(12):6528-39
references.pmid: 16920786
references.citation: Nat Med. 2008 Mar;14(3):282-9
references.pmid: 18264109
references.citation: Eur J Clin Microbiol Infect Dis. 2002 Mar;21(3):161-72
references.pmid: 11957017
references.citation: Curr Opin Pediatr. 1994 Dec;6(6):668-75
references.pmid: 7849812
references.citation: Antimicrob Agents Chemother. 2001 Dec;45(12):3474-81
references.pmid: 11709327
references.citation: Nature. 2002 Nov 14;420(6912):182-6
references.pmid: 12432394
references.citation: Respiration. 1996;63(3):155-9
references.pmid: 8739485
references.citation: Am J Respir Cell Mol Biol. 2011 Jul;45(1):88-94
references.pmid: 20855648
references.citation: Toxicol Appl Pharmacol. 2012 Sep 1;263(2):251-8
references.pmid: 22763362
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1983 Apr;54(4):1120-4
references.pmid: 6853288
references.citation: J Immunol. 2004 Mar 1;172(5):3059-69
references.pmid: 14978111
references.citation: J Allergy Clin Immunol. 2013 Apr;131(4):1117-29, 1129.e1-5
references.pmid: 22795370
references.citation: Cytokine. 1997 Nov;9(11):794-800
references.pmid: 9367539
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L733-43
references.pmid: 18708632
references.citation: Clin Microbiol Rev. 2001 Apr;14(2):336-63
references.pmid: 11292642
references.citation: J Immunol. 2011 Nov 1;187(9):4392-402
references.pmid: 22013205
references.citation: Infect Immun. 2012 Jan;80(1):410-7
references.pmid: 22038916
references.citation: J Infect Dis. 1995 Oct;172(4):1061-75
references.pmid: 7561181
references.citation: J Exp Med. 2003 May 5;197(9):1119-24
references.pmid: 12719478
references.citation: J Immunol. 2011 Sep 1;187(5):2261-7
references.pmid: 21824866
references.citation: Antimicrob Agents Chemother. 2008 Mar;52(3):1171-2
references.pmid: 18086835
references.citation: Nat Med. 2008 Mar;14(3):275-81
references.pmid: 18264110
references.citation: Eur J Immunol. 2005 May;35(5):1539-47
references.pmid: 15816015
references.citation: J Emerg Nurs. 1990 Jul-Aug;16(4):243-4
references.pmid: 2385054
references.citation: Am Rev Respir Dis. 1969 Mar;99(3):374-9
references.pmid: 5765629
references.citation: J Med Microbiol. 2009 Oct;58(Pt 10):1291-1297
references.pmid: 19541789
references.citation: Am J Respir Crit Care Med. 2005 Dec 1;172(11):1371-7
references.pmid: 16141442
references.citation: Infect Dis Clin North Am. 2011 Mar;25(1):201-25
references.pmid: 21316001
references.citation: J Exp Med. 2002 Aug 5;196(3):407-12
references.pmid: 12163569
references.citation: J Immunol. 2004 Dec 15;173(12):7406-15
references.pmid: 15585866
references.citation: J Exp Med. 2007 Apr 16;204(4):793-804
references.pmid: 17389238
references.citation: J Immunol. 2002 Oct 1;169(7):3876-82
references.pmid: 12244185
references.citation: Shock. 2002 Dec;18(6):501-6
references.pmid: 12462556
references.citation: Nat Genet. 1995 Feb;9(2):202-9
references.pmid: 7719350
references.citation: Clin Microbiol Infect. 2006 Apr;12(4):376-80
references.pmid: 16524415
references.citation: Semin Immunol. 2007 Dec;19(6):377-82
references.pmid: 18054248
references.citation: Infect Immun. 2005 Jan;73(1):114-25
references.pmid: 15618146
references.citation: J Exp Med. 1997 Jan 20;185(2):207-18
references.pmid: 9016870
references.citation: Postgrad Med J. 1997 Nov;73(865):697-700
references.pmid: 9519180
references.citation: Chest. 1990 Apr;97(4):820-5
references.pmid: 2323253
references.citation: Eur Respir J. 2006 Mar;27(3):615-26
references.pmid: 16507864
references.citation: J Infect Dis. 2000 Oct;182(4):1276-9
references.pmid: 10979934
references.citation: Lung. 2005 May-Jun;183(3):151-67
references.pmid: 16078037
references.citation: Br J Haematol. 2007 Nov;139(4):519-31
references.pmid: 17979942
references.citation: Clin Infect Dis. 2010 Apr 15;50(8):1091-100
references.pmid: 20218877
references.citation: J Immunol. 2007 May 15;178(10):6367-73
references.pmid: 17475866
references.citation: J Immunol. 2000 Jul 15;165(2):962-8
references.pmid: 10878372
references.citation: Trends Immunol. 2010 Sep;31(9):354-61
references.pmid: 20691634
references.citation: Am J Respir Cell Mol Biol. 2011 Aug;45(2):386-92
references.pmid: 21131440
references.citation: J Occup Med. 1962 Mar;4:152-4
references.pmid: 14452652
references.citation: Infect Immun. 2011 Oct;79(10):3966-77
references.pmid: 21807912
references.citation: N Engl J Med. 2008 Nov 27;359(22):2355-65
references.pmid: 19038881