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

Andre, Eunice; Nassini, Romina; Materazzi, Serena; Andrè, Eunice; Sartiani, Laura; Aldini, Giancarlo; Trevisani, Marcello; Carnini, Chiara; Massi, Daniela; Pedretti, Pamela; Carini, Marina; Cerbai, Elisabetta; Preti, Delia; Villetti, Gino; Civelli, Maurizio; Trevisan, Gabriela; Azzari, Chiara; Stokesberry, Susan; Sadofsky, Laura; McGarvey, Lorcan; Patacchini, Riccardo; Geppetti, Pierangelo

Authors

Eunice Andre

Romina Nassini

Serena Materazzi

Eunice Andrè

Laura Sartiani

Giancarlo Aldini

Marcello Trevisani

Chiara Carnini

Daniela Massi

Pamela Pedretti

Marina Carini

Elisabetta Cerbai

Delia Preti

Gino Villetti

Maurizio Civelli

Gabriela Trevisan

Chiara Azzari

Susan Stokesberry

Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Lecturer in Respiratory Medicine/ Academic lead for postgraduate training in HYMS

Lorcan McGarvey

Riccardo Patacchini

Pierangelo Geppetti



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.—Nassini, R., Materazzi, S., Andrè, E., Sartiani, L., Aldini, G., Trevisani, M., Carnini, C., Massi, D., Pedretti, P., Carini, M., Cerbai, E., Preti, D., Villetti, G., Civelli, M., Trevisan, G., Azzari, C., Stokesberry, S., Sadofsky, L., McGarvey, L., Patacchini, R., Geppetti, P. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation causes neurogenic inflammation in the airways and other tissues in rodents.

Journal Article Type Article
Publication Date 2010-12
Journal FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 1530-6860
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 24
Issue 12
Pages 4904-4916
APA6 Citation Nassini, R., Materazzi, S., Andrè, E., Sartiani, L., Aldini, G., Trevisani, M., …Geppetti, P. (2010). Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB Journal, 24(12), 4904-4916. doi:10.1096/fj.10-162438
DOI https://doi.org/10.1096/fj.10-162438
Keywords Biotechnology; Genetics; Biochemistry; Molecular Biology
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