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Secretory phospholipases A₂ stimulate mucus secretion, induce airway inflammation, and produce secretory hyperresponsiveness to neutrophil elastase in ferret trachea

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 18 May 2006 ; accepted in final form 8 August 2006

Secretory phospholipases A₂ (sPLA₂) are increased in the bronchoalveolar lavage fluid of patients with asthma and acute respiratory distress syndrome. Intratracheal sPLA₂ instillation induces acute lung injury in the rat and guinea pig. We hypothesized that sPLA₂ would stimulate mucus secretion in vitro and that intratracheal sPLA₂ exposure would induce mucus hypersecretion and airway inflammation in the ferret trachea in vivo. In vitro, porcine pancreatic sPLA₂ at a concentration of 0.5 or 5 U/ml significantly increased mucous glycoconjugate (MG) secretion from the excised ferret trachea. P-bromophenacylbromide (a sPLA₂ inhibitor), quercetin (a lipoxygenase inhibitor), or MK-886 (a 5-lipoxygenase inhibitor), each at 10^–4 M, significantly reduced sPLA₂-induced MG secretion. sPLA₂-stimulated MG secretion was decreased in Ca²⁺-free medium. In vivo, ferrets were intubated for 30 min once per day for 3 days using an ETT coated with 20 units of porcine pancreatic sPLA₂ mixed in water-soluble jelly. Constitutive MG secretion increased 1 day after sPLA₂ exposure and returned to control 5 days later. Human neutrophil elastase (HNE) at 10^–8 M increased MG secretion in the sPLA₂-exposed trachea compared with that in the control trachea, but methacholine at 10^–7 M did not. sPLA₂-induced secretory hyperresponsiveness continued for at least 5 days after sPLA₂ exposure ended. sPLA₂ increased tracheal inflammation, MG secretion, and secretory hyperresponsiveness to HNE probably through enzymatic action rather than by activation of its receptor.

mucous glycoconjugate; lipoxygenase; mucin; asthma

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