Effect of salmeterol on Haemophilus influenzae infection of respiratory mucosa in vitro

Abstract

aaNontypable Haemophilus influenzae is a common commensal bacterium in the upper respiratory tract, present in up to three quarters of normal subjects [1]. However, under permissive conditions it may become pathogenic, and frequently causes upper and lower respiratory tract infections, including otitis media, sinusitis, pneumonia and infective exacerbations of chronic obstructive pulmonary disease. H. influenzae is also commonly isolated from purulent sputum of patients with cystic fibrosis and bronchiectasis [2][3][4].Studies of bacterial interactions with respiratory cells or intact mucosa in vitro have provided important information about the pathogenesis of H. influenzae infections, which may in the future lead to the development of new treatments. Infection causes patchy, and sometimes confluent, damage to epithelium [5,6] and bacteria adhere predominantly to mucus, damaged cells and exposed collagen. H. influenzae endotoxin induces the release of proinflammatory mediators (interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)α and intercellular adhesion molecule (ICAM)-1) from human bronchial epithelial cells [7]. H. influenzae also releases uncharacterized factors which impair mucociliary clearance by stimulating mucus secretion [8], causing ciliary beat slowing and dyskinesia, and damaging epithelial cells [9,10]. Immunoglobulin (Ig)A1 proteases reduce mucosal defence mechanisms [11]. These effects all promote bacterial persistence on the mucosa [12].Salmeterol is a potent β 2 -agonist with a prolonged action [13][14][15]. We have recently shown that salmeterol (4×10 -7 M) reduced the damage that occurred to respiratory epithelium during Pseudomonas aeruginosa infection of nasal turbinate organ cultures, and decreased ultrastructural damage to epithelial cells caused by the P. aeruginosa toxins pyocyanin and elastase [16]. In separate experiments [17,18] it was observed, using light microscopy, that the disruption of epithelial integrity caused by pyocyanin was delayed in the presence of salmeterol (2×10 -7 M) and other agents that increased intracellular cyclic adenosine monophosphate (cAMP). Selective antagonists were used to demonstrate that salmeterol reduced epithelial damage via stimulation of β 2 -adrenoceptors. These data suggest that agents that elevate intracellular cAMP may protect respiratory epithelium from damage caused by bacterial infection.Having established that salmeterol reduces P. aeruginosa-induced epithelial damage of nasal turbinate organ cultures [16], we wished to determine whether this effect was species and tissue specific. We have now investigated the effect of salmeterol on the interaction of H. influenzae with the mucosa of an adenoid organ culture with an air-mucosal interface using scanning electron microscopy. Materials and methods BacteriologyH. influenzae strain SH9 is a nontypable clinical isolate that has been studied previously in our laboratory [6]. SH9 These results suggest that salmeterol protects the respiratory epithelium against Haemophilus influenzae-induced...

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