Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung.

Jeryl Sandoval,Clyde J Wright,Robyn De Dios,Eva Nozik-Grayck,Sarah Mckenna,Brittany Butler,Leanna Nguyen,Roy Toston,David J Orlicky,Ayed Allawzi,Cynthia Ju,Caroline T Phan

doi:10.1155/2019/7595126

Abstract

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.

Highlights

Acetaminophen (N-acetyl-p-aminophenol, APAP) is the most commonly used analgesic and antipyretic around the world [1, 2]
Our findings confirm that following toxic APAP exposure, distal lung cytochrome P450 2E1 (CYP2E1) expression is associated with APAP metabolism and tissue injury as well as inflammatory and endoplasmic reticulum (ER) signaling
Less than would be present with other types of inflammatory injury. We speculate this visible increase was not large enough to provide an adequate number of cells to make any conclusions using flow cytometry. These results demonstrate that the APAP-metabolizing enzyme CYP2E1 is expressed and is active in the distal lung and that toxic APAP metabolites accumulate in the distal lung where injury is observed

Summary

Introduction

Acetaminophen (N-acetyl-p-aminophenol, APAP) is the most commonly used analgesic and antipyretic around the world [1, 2]. APAP is perceived to be safe and effective, leading to human exposures that begin in utero with maternal use and continue throughout lifetime. This perception is challenged by the fact that acute overdose of APAP is highly toxic and is the leading cause of acute liver failure in the USA and Europe [1, 2]. One consistent observation has been the association between APAP exposure and pulmonary dysfunction. Both prenatal and early-life APAP exposures have been linked to an increased risk of developing asthma [3, 5,6,7]. Rats and mice exposed to APAP develop bronchiolar injury that occurs within 4 hours of initial

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Conclusion