title: Effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes.
abstract: Inhalation of O3 causes airways neutrophilic inflammation accompanied by other changes including increased levels of cyclo-oxygenase products of arachidonic acid in bronchoalveolar lavage fluid (BALF). Ozone O3 exposure also causes decreased forced vital capacity (FVC) and forced expiratory volume after 1 s (FEV(1)), associated with cough and substernal pain on inspiration, and small increases in specific airway resistance (SRAW). The spirometric decrements are substantially blunted by pretreatment with indomethacin. Since the O3-induced decrement in FVC is due to involuntary inhibition of inspiration, a role for stimulation of nociceptive respiratory tract afferents has been suggested and cyclo-oxygenase products have been hypothesized to mediate this stimulation. However, the relation (if any) between the O3-induced neutrophilic airways inflammation and decreased inspiratory capacity remains unclear. We studied the effects of pharmacologic inhibition of O3-induced spirometric changes on the inflammatory changes. Each of ten healthy men was exposed twice (5-week interval) to 0.4 ppm O3 for 2 h, including 1 h of intermittent exercise (ventilation 601*min(-1)). One-and-a-half hours prior to and midway during each exposure the subject ingested 800 mg and 200 mg, respectively, of the non-steroidal anti-inflammatory drug ibuprofen (IBU), or placebo [PLA (sucrose)], in randomized, double-blind fashion. Spirometry and body plethysmography were performed prior to drug administration, and before and after O3 exposure. Immediately following postexposure testing, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed. Neither IBU nor PLA administration changed pre-exposure lung function. O3 exposure (with PLA) caused a significant 17 percent mean decrement in FEV(1) (P <0.01) and a 56 percent increase in mean SRAW. Following IBU pretreatment, O3 exposure induced a significantly lesser mean decrement in FEV(1) (7 percent) but still a 50 percent increase in mean SRAW. IBU pretreatment significantly decreased post-O3 BAL levels of prostaglandin E2 (PGE2) by 60.4 percent (P <0.05) and thromboxane B(2) (TxB(2)) by 25.5 percent (P <0.05). Of the proteins, only interleukin-6 was significantly reduced (45 percent, P <0.05) by IBU as compared to PLA pretreatment. As expected, O3 exposure produced neutrophilia in BALF. There was, however, no effect of IBU on this finding. None of the major cell types in the BALF differed significantly between pretreatments. We found no association between post-exposure changes of BALF components and pulmonary function decrements. We conclude that IBU causes significant inhibition of O3-induced increases in respiratory tract PGE(2) and TxB(2) levels concomitant with a blunting of the spirometric response. This is consistent with the hypothesis that the products of AA metabolism mediate inhibition of inspiration. However, IBU did not alter the modest SRAW response to O3.
authors.affiliation: Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7310, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hazucha
authors.forename: M
authors.initials: M
authors.lastname: Madden
authors.forename: G
authors.initials: G
authors.lastname: Pape
authors.forename: S
authors.initials: S
authors.lastname: Becker
authors.forename: R
authors.initials: R
authors.lastname: Devlin
authors.forename: H S
authors.initials: HS
authors.lastname: Koren
authors.forename: H
authors.initials: H
authors.lastname: Kehrl
authors.forename: P A
authors.initials: PA
authors.lastname: Bromberg
mesh_terms: D000328:Adult; D001991:Bronchitis / Q000139:chemically induced*; D001992:Bronchoalveolar Lavage Fluid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010126:Ozone / Q000494:pharmacology*; D011650:Pulmonary Alveoli; D012129:Respiratory Function Tests; D013147:Spirometry
chemical_list: D016861:Cyclooxygenase Inhibitors; D010126:Ozone; D007052:Ibuprofen