Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung.
Acetaminophen
/ adverse effects
Animals
Cells, Cultured
Cytochrome P-450 CYP2E1
/ genetics
Disease Models, Animal
Drug-Related Side Effects and Adverse Reactions
/ metabolism
Emphysema
/ etiology
Endoplasmic Reticulum Stress
Humans
Inflammation Mediators
/ metabolism
Lung
/ metabolism
Male
Mice
Mice, Inbred ICR
Signal Transduction
Journal
Oxidative medicine and cellular longevity
ISSN: 1942-0994
Titre abrégé: Oxid Med Cell Longev
Pays: United States
ID NLM: 101479826
Informations de publication
Date de publication:
2019
2019
Historique:
received:
17
08
2019
revised:
21
10
2019
accepted:
04
11
2019
entrez:
31
12
2019
pubmed:
31
12
2019
medline:
26
6
2020
Statut:
epublish
Résumé
Clinical studies have demonstrated a strong association between both acute toxic exposure and the repetitive, chronic exposure to acetaminophen (APAP) with pulmonary dysfunction. However, the mechanisms underlying this association are unknown. Preclinical reports have demonstrated that significant bronchiolar injury occurs with toxic APAP exposure, but very little information exists on how the distal lung is affected. However, cells in the alveolar space, including the pulmonary epithelium and resident macrophages, express the APAP-metabolizing enzyme CYP2E1 and are a potential source of toxic metabolites and subsequent distal lung injury. Thus, we hypothesized that distal lung injury would occur in a murine model of toxic APAP exposure. Following exposure of APAP (280 mg/kg, IP), adult male mice were found to have significant proximal lung histopathology as well as distal lung inflammation and emphysematous changes. Toxic APAP exposure was associated with increased CYP2E1 expression in the distal lung and accumulation of APAP-protein adducts. This injury was associated with distal lung activation of oxidant stress, endoplasmic reticulum stress, and inflammatory stress response pathways. Our findings confirm that following toxic APAP exposure, distal lung CYP2E1 expression is associated with APAP metabolism, tissue injury, and oxidant, inflammatory, and endoplasmic reticulum signaling. This previously unrecognized injury may help improve our understanding of the relationship between APAP and pulmonary-related morbidity.
Identifiants
pubmed: 31885815
doi: 10.1155/2019/7595126
pmc: PMC6914885
doi:
Substances chimiques
Inflammation Mediators
0
Acetaminophen
362O9ITL9D
Cytochrome P-450 CYP2E1
EC 1.14.13.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7595126Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL132941
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL139726
Pays : United States
Informations de copyright
Copyright © 2019 Jeryl Sandoval et al.
Déclaration de conflit d'intérêts
The authors declare no potential financial or ethical conflicts of interest.
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