Secretory phospholipases A₂stimulate mucus secretion, induce airway inflammation, and produce secretory hyperresponsiveness to neutrophil elastase in ferret trachea

Abstract

Secretory phospholipases A(2) (sPLA(2)) are increased in the bronchoalveolar lavage fluid of patients with asthma and acute respiratory distress syndrome. Intratracheal sPLA(2) instillation induces acute lung injury in the rat and guinea pig. We hypothesized that sPLA(2) would stimulate mucus secretion in vitro and that intratracheal sPLA(2) exposure would induce mucus hypersecretion and airway inflammation in the ferret trachea in vivo. In vitro, porcine pancreatic sPLA(2) at a concentration of 0.5 or 5 U/ml significantly increased mucous glycoconjugate (MG) secretion from the excised ferret trachea. P-bromophenacylbromide (a sPLA(2) inhibitor), quercetin (a lipoxygenase inhibitor), or MK-886 (a 5-lipoxygenase inhibitor), each at 10(-4) M, significantly reduced sPLA(2)-induced MG secretion. sPLA(2)-stimulated MG secretion was decreased in Ca(2+)-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 sPLA(2) mixed in water-soluble jelly. Constitutive MG secretion increased 1 day after sPLA(2) exposure and returned to control 5 days later. Human neutrophil elastase (HNE) at 10(-8) M increased MG secretion in the sPLA(2)-exposed trachea compared with that in the control trachea, but methacholine at 10(-7) M did not. sPLA(2)-induced secretory hyperresponsiveness continued for at least 5 days after sPLA(2) exposure ended. sPLA(2) increased tracheal inflammation, MG secretion, and secretory hyperresponsiveness to HNE probably through enzymatic action rather than by activation of its receptor.

Critical role of cytosolic phospholipase A2α in bronchial mucus hypersecretion in CFTR-deficient mice

“…Although our studies clearly indicate that cPLA2a plays a key role in mucus production, the implication of other PLA2 in this process cannot be excluded. Indeed, it has been shown that secreted PLA2 stimulate mucus secretion in ferret trachea [40].…”

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

“…[8][9][10] We have reported that sPLA 2 stimulate mucus hypersecretion in the ferret trachea through activation of the lipoxygenase (LO) pathway. 11 Mucus obstruction of airways and goblet cell hyperplasia are characteristic of severe asthma. 12,13 IL-13 is increased in asthma and induces goblet cell hyperplasia with mucus hypersecretion in vivo and in vitro.…”

“…35 We have shown previously that sPLA 2 dramatically increases mucus secretion from the ferret trachea and we called this "secretory hyperresponsiveness." 11 Mucus accumulation and goblet cell hyperplasia in the airway are closely correlated with morbidity and mortality. 36,37 Th e results of the current study suggest that sPLA 2 from ciliated cells, perhaps acting as airway sensory receptors, can increase mucus secretion and production of inflammatory mediators from IL-13-transformed goblet cells.…”

Multiple Roles of Phospholipase A2during Lung Infection and Inflammation

“…Several studies have detected the presence of sPLA 2 in the lung (5,88). In conditions such as asthma, ARDS, and bronchial pneumonia, elevated amounts of sPLA 2 are found in the bronchial/alveolar lavage fluid (BALF) and lung tissue of patients (5,7,18,50,72,88,108).…”

“…In conditions such as asthma, ARDS, and bronchial pneumonia, elevated amounts of sPLA 2 are found in the bronchial/alveolar lavage fluid (BALF) and lung tissue of patients (5,7,18,50,72,88,108). In fact, a positive correlation exists between increased levels of sPLA 2 and a poor clinical outcome (5,88). A major source of sPLA 2 is the alveolar macrophage (5).…”