Date of Completion
Acetaminophen, Asthma, Tobacco Smoke, Lungs, Pulmonary, Toxicology, Oxidative Stress
John B. Morris
Jose E. Manautou
Michelle M. Cloutier
Roger S. Thrall
Field of Study
Doctor of Philosophy
The prevalence of asthma is increasing, and the cause(s) of this increase are unknown. The etiology of asthma is complex and includes both genetic, developmental, and environmental components. Epidemiological evidence suggests that acetaminophen (APAP, N-acetyl-p-aminophenol) may play a role in the pathogenesis of asthma. The goal of this thesis was to test the plausibility of the “acetaminophen hypothesis” in asthma, which states that therapeutic use of acetaminophen is linked to the increase in asthma prevalence through pro-oxidant effects of the drug.
The airways of the respiratory system represent the largest surface area of the body exposed to the atmosphere. Several physiological adaptations of the respiratory tract aid in maintaining homeostasis under variable atmospheric conditions. These include oxidant responses, sensory irritation-reflex responses, and inflammatory responses. Respiratory tract responses can be activated by environmental exposures and disease states. In some situations they can be compromised. For example, asthmatic airways mount exaggerated immune responses to normally innocuous atmospheric variables, and may have altered oxidant responses. The measurement of respiratory responses can provide direct data on airway status.
Described herein are studies examining the effects of acetaminophen on acute airway oxidant responses, acute sensory irritation-reflex responses, and longer-term inflammatory responses in a murine model of allergic airway disease (asthma). The first study assessed murine acute respiratory oxidant responses after APAP treatment alone, or in combination with environmental tobacco smoke (ETS). Near-therapeutic doses of APAP induced airway oxidant responses similarly to ETS. Notably, APAP potentiated both ETS induced oxidant responses and ETS induced sensory irritant-reflex irritant responses. In a second study, the effects of acetaminophen on airway inflammatory responses to house dust mite extract (HDM) were examined. Unexpectedly, the effects of HDM exposure were substantially diminished by APAP. These studies suggest that APAP has acute pro-oxidant effects in the airways at near-therapeutic doses, and thus may have detrimental effects in individuals predisposed to oxidant injury, or exposed to oxidant air pollutants such as ETS. Despite documenting pro-oxidant effects of APAP in the airways, these studies call into question the overall biological plausibility of the “APAP hypothesis” in asthma.
Smith, Gregory J., "Modulation of Respiratory Tract Responses by Acetaminophen" (2015). Doctoral Dissertations. 830.