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

被引：100

作者：

Nassini, Romina ^{[1
]}

Materazzi, Serena ^{[1
]}

Andre, Eunice ^{[1
]}

Sartiani, Laura ^{[1
]}

Aldini, Giancarlo ^{[4
]}

Trevisani, Marcello ^{[5
]}

Carnini, Chiara ^{[6
]}

Massi, Daniela ^{[2
]}

Pedretti, Pamela ^{[1
]}

Carini, Marina ^{[4
]}

Cerbai, Elisabetta ^{[1
]}

Preti, Delia ^{[7
]}

Villetti, Gino ^{[6
]}

Civelli, Maurizio ^{[6
]}

Trevisan, Gabriela ^{[1
]}

Azzari, Chiara ^{[3
]}

Stokesberry, Susan ^{[8
]}

Sadofsky, Laura ^{[9
]}

McGarvey, Lorcan ^{[8
]}

Patacchini, Riccardo ^{[6
]}

Geppetti, Pierangelo ^{[1
]}

机构：

[1] Univ Florence, Dept Preclin & Clin Pharmacol, I-50139 Florence, Italy

[2] Univ Florence, Dept Human Pathol & Oncol, I-50139 Florence, Italy

[3] Univ Florence, Dept Pediat, I-50139 Florence, Italy

[4] Univ Milan, Dept Pharmaceut Sci, Milan, Italy

[5] Pharmeste Srl, Ferrara, Italy

[6] Chiesi Farmaceutici SpA, Dept Pharmacol, Parma, Italy

[7] Univ Ferrara, Dept Pharmaceut Chem, I-44100 Ferrara, Italy

[8] Queens Univ Belfast, Ctr Infect & Immun, Belfast, Antrim, North Ireland

[9] Univ Hull, Castle Hill Hosp, Div Cardiovasc & Resp Studies, Kingston Upon Hull HU6 7RX, N Humberside, England

来源：

FASEB JOURNAL | 2010年 / 24卷 / 12期

关键词：

primary sensory neurons; substance P; asthma; chronic obstructive pulmonary disease; GENE-RELATED PEPTIDE; PARACETAMOL USE; BENZOQUINONE IMINE; SENSORY NERVES; ASTHMA; CHILDREN; RISK; ACTIVATION; DISEASE; TRPA1;

D O I：

10.1096/fj.10-162438

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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., Andre, 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. FASEB J. 24, 4904-4916 (2010). www.fasebj.org

引用

页码：4904 / 4916

页数：13

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