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Biological Plausibility
There is also a good deal of evidence supporting biological plausibility of the detrimental effect of acetaminophen on the airways. The main mechanism suggested is that acetaminophen may impair respiratory antioxidant defenses by decreasing the amount of reduced glutathione present in the airways. This would increase the presence of oxygen radicals in the airways, where they may produce their well-known array of detrimental effects: tissue injury, smooth muscle contraction, bronchial hyper-responsiveness, increased vascular permeability, release of proinflammatory mediators and impaired β-receptor function – all effects potentially relevant to the pathogenesis of asthma and promoting airway inflammation. It is known that glutathione is present in increased concentrations in the alveolar fluid of patients with asthma and that alveolar glutathione levels correlates with the degree of bronchial hyperresponsiveness, suggesting that patients with asthma have increased antioxidant defenses in order to balance the increase in oxygen radical generation also observed in patients with asthma. Lower levels of glutathione may also influence the Th1-Th2 cytokine response patterns. It has been shown, in animal models, that depleting glutathione in antigen-presenting cells in vivo and in vitro may produce a shift away from Th1 towards Th2 cytokine production that may predispose to atopic diseases like asthma. It has also been shown that acetaminophen reduces the immune response to, and prolongs, rhinovirus infection in human volunteers. Finally, another possible mechanism could be related to its antipyretic effect: by reducing fever, acetaminophen may reduce the cytokine storm that takes place as a part of the febrile response, mainly the production of IFN-γ and IL-2, which have predominant Th1 profiles. However, while acetaminophen reduces fever, there is conflicting evidence as to whether it also influences the profile of cytokine production and its effect may depend on the cause of fever. Figure 1 offers an overview of the main mechanisms that may explain the detrimental effect of acetaminophen on the airways. It is worth noting that most of these data were generated in the early 1990s, well before the hypothesis of the detrimental effect of acetaminophen in asthma was proposed and had any supporting epidemiological evidence.
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Figure 1.
Biological plausibility of the detrimental effect of acetaminophen on the airways.
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