Treatment Of Airway Inflammatory Diseases Research Articles

Nitric oxide and airway disease.

Nitric oxide (NO) may play an important role in regulating airway function and in the pathophysiology of inflammatory airway diseases. Endothelium-derived NO may be important in regulating airway blood flow and, indirectly, plasma exudation. NO is the neurotransmitter of bronchodilator nerves in human airways and counteracts the bronchoconstriction due to cholinergic neural mechanisms. Inducible NO synthase (iNOS) is expressed in human epithelial cells in response to pro-inflammatory cytokines and oxidants, probably via activation of the transcription factor nuclear factor kappa B (NF-kappa B). There is increased expression of iNOS in the epithelium of asthmatic patients and in lung macrophages in bronchiectasis. This may account for the increased concentration of NO in the exhaled air of patients with inflammatory airways disease. Increased NO production in the airways may result in hyperaemia, plasma exudation, mucus secretion and indirectly increased proliferation of Th2 lymphocytes responsible for eosinophilic inflammation. Glucocorticoids inhibit the induction of iNOS in epithelial cells and reduce the elevated exhaled NO to normal values. Selective inhibitors of iNOS may be useful in the treatment of inflammatory airway diseases, such as asthma, in the future.

Evidence for an atypical, or beta 3-adrenoceptor in ferret tracheal epithelium.

1. A preparation of the ferret trachea in vitro was used to examine the effects of three selective beta-adrenoceptor agonists on lysozyme secretion from submucosal gland serous cells and epithelial albumin transport into tracheal mucus following sustained, submaximal stimulation of mucus production with methacholine (20 microM). 2. Prenalterol, salbutamol and BRL 37344 all enhanced methacholine-induced albumin output. BRL 37344 was 10,000 times more potent than salbutamol, and salbutamol was slightly more potent than prenalterol. The concentrations required to increase albumin output by 100% (EC100%) were 1.4 nM, 0.7 mM and approximately 1.0 mM for BRL 37344, salbutamol and prenalterol, respectively. All three agonists inhibited methacholine-induced lysozyme output, with salbutamol being 60 times more potent than BRL 37344, and BRL 37344 being approximately 100 times more potent than prenalterol. 3. The selective beta 2-adrenoceptor antagonist, ICI 118551, inhibited the increase in albumin output produced by BRL 37344, but much more potent at inhibiting the response to salbutamol; the pA2 for ICI 118551 was 5.55 and 7.18 (P less than 0.001) when the agonist was BRL 37344 and salbutamol, respectively. ICI 118551 also attenuated the inhibition of lysozyme output produced by the two agonists, but was 10-30 times more potent at inhibiting this response than the albumin response to BRL 37344 and salbutamol. 4. The greater potency (4-5 orders of magnitude) of BRL 37344, compared to the beta 1- (prenalterol) and beta 2- (salbutamol) adrenoceptor selective agonists, in stimulating methacholine-induced albumin transport suggests that tracheal epithelium possess an atypical, or beta 3-adrenoceptor similar to that previously reported for adipocytes and gastrointestinal smooth muscle. The weak antagonism of the response to BRL 37344 by ICI 118551 would also be consistent with an atypical adrenoceptor mediating the albumin transport response. Inhibition of methacholine-induced serous cell lysozyme output would appear to be mediated predominantly by beta2-adrenoceptors.5. In view of the possible beneficial protective effects of albumin in airway surface liquid, selective beta3-agonists like BRL 37344 might have potential value in the prevention and/or treatment of inflammatory airway disease.

Isolation of an inhibitor of neutrophil function from bronchial lavage of normal volunteers

Bronchial inflammation is associated with a reduction in airway caliber. Factors that may dampen this inflammation are ill defined. We have developed a model of airway inflammation using an extract of cotton bracts (CBE). In the current study we characterize inhibitor(s) of polymorphonuclear neutrophil (PMN) function in bronchial lavage (BL) fluid and examine the relationship between inhibitor concentrations and induction of bronchial inflammation or bronchoconstriction by CBE. We report that BL obtained contains factors that inhibit PMN hydrogen peroxide production and chemotaxis to formylmethionylleucyl-phenylalanine (FMLP). In two different subject populations the relative degree of a one molecular mass inhibitor was greatest in BL from subjects that manifested little bronchoconstriction to CBE compared with other subjects. In one subject population the relative amount of this inhibitor correlated inversely with the bronchoconstricting response to CBE and a number of parameters of airway inflammation including PMN noted on bronchial biopsy after CBE instillation. Partial chemical characterization of one molecular mass BL-derived inhibitor reveals it is of low molecular mass (less than 1,000 Da), nonpolar, and sensitive to aminopeptidase digestion. The finding that the bronchial environment contains variable concentrations of an oligopeptide that inhibits PMN function has important implications for treatment of inflammatory airway diseases.