Acetaminophen,viaits reactive metaboliteN-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents

Abstract

Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Intriguingly, treatment with the nonselective COX inhibitor indomethacin increased capsaicininduced cough thresholds in patients with asthma or chronic bronchitis but not in healthy subjects (Fujimura et al, 1995). By contrast, at least in rodents, acetaminophen causes airway hyper-reactivity through TRPA1 (Nassini et al, 2010b). These results offer compelling evidence that inflammatory mediators produced in diseased airways enhance airway reflex sensitivity in a manner that can be at least partially reversed by pharmacological intervention.…”

Transient Receptor Potential A1 Channels

“…However, in the past 10 years a wide series of epidemiologic studies has shown that exposure to therapeutic doses of APAP is one of the risk factors for asthma and COPD. 62 Interestingly, N -acetyl-p -benzo-quinoneimine, like other electrophilic molecules, is a TRPA1 activator, which can evoke neurogenic infl ammation through the release of neuropeptides from sensory nerve endings. These TRPA1-mediated events may contribute to the increased risk of asthma and COPD associated with the therapeutic use of paracetamol.…”

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

“…Taken together, our findings demonstrate that DPI and other NOX inhibitors activate human TRPA1 without mediating NOX. calcium channel; transient receptor potential; NADPH oxidase inhibitors TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), a Ca 2ϩ -permeable nonselective cation channel widely expressed in neuronal and nonneuronal cells, is activated by noxious cold, mechanical stimulation, irritant chemicals, and some clinical drugs (1,7,12,17,26,28,30,36). Because transgenic mice lacking TRPA1 have suppressed sensitivity to mechanical stimulation, cold stimuli, and TNF␣-induced mechanical hyperalgesia (5,8,20,23,33), the channel has been proposed to be a nociceptor mediating acute and inflammatory pain (3,23,33).…”