Abstract
This study investigated whether a correlation between airway hyperreactivity (AHR), leukocyte influx, and nitric oxide (NO) existed in guinea pigs chronically exposed to lipopolysaccharide (LPS). The effect of the corticosteroid, dexamethasone, or phosphodiesterase-4 (PDE4) inhibitor, rolipram, on these features was studied. Airway function was measured in conscious guinea pigs (specific airways conductance) before and after single, double, or chronic (nine) LPS (30 μg · ml−1, 1 h) exposures. Airway reactivity to inhaled histamine (1 mM, 20 s) was assessed before and at various times after LPS challenges. Leukocytes and NO metabolites were measured in bronchoalveolar lavage fluid (BALF). AHR occurred at 1 h after a single LPS challenge and was resolved by 4 h. This coincided with reduction and recovery, respectively, of BALF NO levels. The AHR and NO deficiency were extended to 4 h, after a double LPS exposure. Chronic LPS exposures, 48 h apart, initially caused persistent bronchodilations, whereas later exposures produced progressively persistent bronchoconstrictions. There was AHR 24 h after the eighth challenge. Twenty-four hours after the ninth LPS exposure, macrophages, neutrophils, eosinophils, and NO metabolites were elevated in BALF. Dexamethasone (20 mg · kg−1i.p.) or rolipram (1 mg · kg−1 i.p.) prevented single and chronic LPS-induced AHR, the respective deficiency and elevation in NO metabolites, and the chronic LPS-induced leukocyte influx. Dexamethasone exacerbated, whereas rolipram reversed, the chronic LPS-induced bronchoconstrictions. This study demonstrates for the first time that chronic LPS causes persistent bronchoconstriction, neutrophilic inflammation, AHR, and NO overproduction in guinea pig airways. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in airway disease.
Footnotes
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↵1 Preliminary findings from these studies have been presented to the British Pharmacological Society and the Royal Pharmaceutical Society of Great Britain Conference: Toward TJ and Broadley KJ (1999) Characteristics of airway hyperreactivity, cell influx and steroid sensitivity after inhaled LPS in conscious guinea-pigs. Br J Pharmacol128:275P. Toward TJ and Broadley KJ (1999) Effect of single and double exposures to LPS on lung function, airway reactivity and leukocyte infiltration.J Pharm Pharmacol51:144. Toward TJ and Broadley KJ (2000) The role of NO on changes in airway reactivity induced by exposure of guinea-pigs to inhaled LPS. Br J Pharmacol129:228P.
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This work was supported by a Glaxo-Wellcome Studentship to T.J.T.
- Abbreviations:
- AHR
- airway hyperreactivity
- COPD
- chronic obstructive pulmonary disease
- NO
- nitric oxide
- cNOS
- constitutive nitric-oxide synthase
- nNOS
- neuronal nitric-oxide synthase
- eNOS
- endothelial nitric-oxide synthase
- iNOS
- inducible nitric-oxide synthase
- TNF-α
- tumor necrosis factor-α
- LPS
- lipopolysaccharide
- NF-κB
- nuclear factor-κB
- FEV1
- forced expiratory volume in 1 s
- PDE4
- phosphodiesterase isoenzyme 4
- BAL
- bronchoalveolar lavage
- sGaw
- specific airways conductance
- DMSO
- dimethyl sulfoxide
- l-NAME
- Nω-nitro-l-arginine methyl ester
- Received January 22, 2001.
- Accepted March 30, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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