Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung
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 b...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Hindawi Limited
2019-01-01
|
Series: | Oxidative Medicine and Cellular Longevity |
Online Access: | http://dx.doi.org/10.1155/2019/7595126 |
id |
doaj-e690166adc3d4b7c81c756b0a3971624 |
---|---|
record_format |
Article |
spelling |
doaj-e690166adc3d4b7c81c756b0a39716242020-11-25T01:14:06ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942019-01-01201910.1155/2019/75951267595126Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine LungJeryl Sandoval0David J. Orlicky1Ayed Allawzi2Brittany Butler3Cynthia Ju4Caroline T. Phan5Roy Toston6Robyn De Dios7Leanna Nguyen8Sarah McKenna9Eva Nozik-Grayck10Clyde J. Wright11Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Pathology, University of Colorado School of Medicine, Aurora, CO, USADevelopmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADevelopmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USASection of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USAClinical 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.http://dx.doi.org/10.1155/2019/7595126 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jeryl Sandoval David J. Orlicky Ayed Allawzi Brittany Butler Cynthia Ju Caroline T. Phan Roy Toston Robyn De Dios Leanna Nguyen Sarah McKenna Eva Nozik-Grayck Clyde J. Wright |
spellingShingle |
Jeryl Sandoval David J. Orlicky Ayed Allawzi Brittany Butler Cynthia Ju Caroline T. Phan Roy Toston Robyn De Dios Leanna Nguyen Sarah McKenna Eva Nozik-Grayck Clyde J. Wright Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung Oxidative Medicine and Cellular Longevity |
author_facet |
Jeryl Sandoval David J. Orlicky Ayed Allawzi Brittany Butler Cynthia Ju Caroline T. Phan Roy Toston Robyn De Dios Leanna Nguyen Sarah McKenna Eva Nozik-Grayck Clyde J. Wright |
author_sort |
Jeryl Sandoval |
title |
Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung |
title_short |
Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung |
title_full |
Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung |
title_fullStr |
Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung |
title_full_unstemmed |
Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung |
title_sort |
toxic acetaminophen exposure induces distal lung er stress, proinflammatory signaling, and emphysematous changes in the adult murine lung |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2019-01-01 |
description |
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. |
url |
http://dx.doi.org/10.1155/2019/7595126 |
work_keys_str_mv |
AT jerylsandoval toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT davidjorlicky toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT ayedallawzi toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT brittanybutler toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT cynthiaju toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT carolinetphan toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT roytoston toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT robyndedios toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT leannanguyen toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT sarahmckenna toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT evanozikgrayck toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung AT clydejwright toxicacetaminophenexposureinducesdistallungerstressproinflammatorysignalingandemphysematouschangesintheadultmurinelung |
_version_ |
1725158942008410112 |