title: Early immunopathological events in acute model of mycobacterial hypersensitivity pneumonitis in mice.
abstract: Prolonged exposure to antigens of non-tuberculous mycobacteria species colonizing industrial metalworking fluid (MWF), particularly Mycobacterium immunogenum (MI), has been implicated in chronic forms of hypersensitivity pneumonitis (HP) in machinists based on epidemiology studies and long-term exposure of mouse models. However, a role of short-term acute exposure to these antigens has not been described in the context of acute forms of HP. This study investigated short-term acute exposure of mice to MI cell lysate (or live cell suspension) via oropharyngeal aspiration. The results showed there was a dose- and time-dependent increase (peaking at 2 h post-instillation) in lung immunological responses in terms of the pro- (TNFα, IL-6, IL-1β) and anti-inflammatory (IL-10) cytokines. Bronchoalveolar lavage and histology showed neutrophils as the predominant infiltrating cell type, with lymphocytes <5% at all timepoints or concentrations. Granulomatous inflammation peaked between 8 and 24 h post-exposure, and resolved by 96 h. Live bacterial challenge, typically encountered in real-world exposures, showed no significant differences from bacterial lysate except for induction of appreciable levels of interferon (IFN)-γ, implying additional immunogenic potential. Collectively, the short-term mycobacterial challenge in mice led to a transient early immunopathologic response, with little adaptive immunity, which is consistent with events associated with human acute forms of HP. Screening of MWF-originated mycobacterial genotypes/variants (six of MI, four of M. chelonae, two of M. abscessus) showed both inter- and intra-species differences, with MI genotype MJY10 being the most immunogenic. In conclusion, this study characterized the first short-term mycobacterial exposure mouse model that mimics acute HP in machinists; this could serve as a potentially useful model for rapid screening of field MWF-associated mycobacteria for routine and timely occupational risk assessment and for investigating early biomarkers and mechanisms of this understudied immune lung disease.
authors.affiliation: a Department of Environmental Health, Microbial Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Johansson
authors.affiliation: b Department of Pathology and Orthopedic Surgery , Wright State University , Dayton , OH , USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Boivin
authors.affiliation: a Department of Environmental Health, Microbial Pathogenesis and Immunotoxicology Laboratory, Division of Environmental Genetics and Molecular Toxicology , University of Cincinnati College of Medicine , Cincinnati , OH , USA.
authors.forename: Jagjit S
authors.initials: JS
authors.lastname: Yadav
mesh_terms: D000208:Acute Disease; D000542:Alveolitis, Extrinsic Allergic / Q000453:epidemiology / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008669:Metallurgy; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D009164:Mycobacterium Infections / Q000453:epidemiology / Q000276:immunology*; D016273:Occupational Exposure / Q000706:statistics & numerical data; D012306:Risk; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines
keywords: Mycobacterium immunogenum; acute exposure; bronchoalveolar lavage; cytokines; hypersensitivity pneumonitis; immunopathological changes; inhalation; lung pathology; metalworking fluid; mouse