title: Role of sensory nerve peptides rather than mast cell histamine in paclitaxel hypersensitivity.
abstract: Paclitaxel is one of the most extensively used anticancer agents, however, its use is often limited by severe hypersensitivity reactions, including respiratory distress, bronchospasm, and hypotension, which can occur despite premedication with dexamethasone and histamine H1 and H2 antagonists. The present study was designed to determine the mechanisms of paclitaxel hypersensitivity. In rats, paclitaxel (15 mg/kg, intravenously) caused a marked increase in pulmonary vascular permeability and edema. PaO2 decreased, whereas PaCO2 increased, transiently after paclitaxel injection. The paclitaxel-induced pulmonary vascular hyperpermeability was blocked by dexamethasone but not by histamine H1 or H2 antagonists. Paclitaxel increased the vascular permeability in lungs of mast cell-deficient rats Ws/Ws(-/-) to almost the similar extent as that elicited in wild-type rats. On the other hand, the paclitaxel-induced pulmonary vascular hyperpermeability was reversed by sensory denervation with capsaicin or pretreatment with LY303870 and SR48968, NK1 and NK2 antagonists, respectively. Consistent with these findings, a marked elevation of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide was observed in rat bronchoalveolar lavage fluid after paclitaxel injection. These findings suggest that sensory nerves rather than mast cells are implicated in the etiology of paclitaxel hypersensitivity.
authors.affiliation: Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Itoh
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirakawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Goromaru
authors.forename: Shinya
authors.initials: S
authors.lastname: Takasaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yahata
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nakano
authors.forename: Ryozo
authors.initials: R
authors.lastname: Oishi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D004195:Disease Models, Animal; D004342:Drug Hypersensitivity / Q000175:diagnosis*; D006632:Histamine / Q000032:analysis / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000502:physiology; D015288:Neurokinin A / Q000032:analysis; D009479:Neuropeptides / Q000276:immunology / Q000378:metabolism*; D017239:Paclitaxel / Q000276:immunology / Q000494:pharmacology*; D011336:Probability; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D011984:Sensory Receptor Cells / Q000378:metabolism; D013373:Substance P / Q000032:analysis
chemical_list: D009479:Neuropeptides; D013373:Substance P; D006632:Histamine; D015288:Neurokinin A; D015740:Calcitonin Gene-Related Peptide; D017239:Paclitaxel