Effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes

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 (FEV₁), 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 60l · 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% mean decrement in FE₁ (P < 0.01) and a 56% increase in mean SRAW. Following IBU pretreatment, O₃ exposure induced a significantly lesser mean decrement in FEV₁ (7%) but still a 50% increase in mean SRAW. IBU pretreatment significantly decreased post-O₃ BAL levels of prostaglandin E₂ (PGE₂) by 60.4% (P < 0.05) and thromboxane B₂ (TxB₂) by 25.5% (P < 0.05). Of the proteins, only interleukin-6 was significantly reduced (45%, 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 PGE₂ and TxB₂ 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. The neutrophilic component of the inflammatory response to O₃ was not significantly affected by IBU and does not appear to be directly related to the spirometric response.