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Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat


Pellegrini, Giovanni; Williams, Dominic Paul; Amadio, Daniele; Park, Brian Kevin; Kipar, Anja (2020). Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat. Toxicologic pathology, 48(6):725-737.

Abstract

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury. We identified pulmonary endothelial cells as the main target of acute MPTU injury; they exhibited ultrastructural alterations that can result in increased vascular permeability. In tolerant rats, the lungs showed only transient endothelial changes, at 24-hour post dosing, and mild type II pneumocyte hyperplasia on day 7 post dosing. They exhibited glutathione levels similar to the controls and increased expression of flavin-containing monooxygenase 1 (FMO1), the enzyme responsible for bioactivation of small thioureas in the laboratory rat. Incubation of rat pulmonary microsomal preparations with MPTU inhibited FMO activity, indicating that tolerance is related to irreversible inhibition of FMOs. The rat model of thiourea-induced pulmonary toxicity and tolerance represents an interesting approach to investigate certain aspects of the pathogenesis of ALI and therapeutic approaches to lung diseases, such as acute respiratory distress syndrome.

Abstract

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury. We identified pulmonary endothelial cells as the main target of acute MPTU injury; they exhibited ultrastructural alterations that can result in increased vascular permeability. In tolerant rats, the lungs showed only transient endothelial changes, at 24-hour post dosing, and mild type II pneumocyte hyperplasia on day 7 post dosing. They exhibited glutathione levels similar to the controls and increased expression of flavin-containing monooxygenase 1 (FMO1), the enzyme responsible for bioactivation of small thioureas in the laboratory rat. Incubation of rat pulmonary microsomal preparations with MPTU inhibited FMO activity, indicating that tolerance is related to irreversible inhibition of FMOs. The rat model of thiourea-induced pulmonary toxicity and tolerance represents an interesting approach to investigate certain aspects of the pathogenesis of ALI and therapeutic approaches to lung diseases, such as acute respiratory distress syndrome.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pathology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Pathology and Forensic Medicine
Life Sciences > Molecular Biology
Life Sciences > Toxicology
Life Sciences > Cell Biology
Uncontrolled Keywords:Toxicology, Pathology and Forensic Medicine, Cell Biology, Molecular Biology
Language:English
Date:1 August 2020
Deposited On:30 Sep 2020 10:12
Last Modified:01 Oct 2020 20:00
Publisher:Sage Publications
ISSN:0192-6233
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1177/0192623320941465

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