Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation

Abstract

It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg+) mice, airway-targeted overexpression of the epithelial Na+ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg+ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg+ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll/Interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg+ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg+ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg+ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation.

UDP-glucose promotes neutrophil recruitment in the lung

“…Levels of the neutrophil chemoattractant cytokine mKC also were elevated (Fig. 5b), consistent with the inflammatory phenotype described in 10-day-old βENaC-Tg mice [41,42]. Notably, PMN infiltration and mKC levels were markedly PBS or UDP-glucose was instilled into wild-type mouse trachea and BAL was performed after 12 h (a, b) or at the times indicated (c).…”

“…Previous studies indicated that βENaC-Tg mouse lung inflammation is acquired over the perinatal period [34,41,42]. Therefore, we examined the effect of PPTN on neutrophil lung recruitment after daily intranasal instillation of the P2Y 14 R antagonist to neonatal mice for 12 days.…”

CFTR: cystic fibrosis and beyond

“…Collectively, these studies demonstrated that this mouse model exhibits many characteristic features of early CF lung disease [27][28][29]. Of note, the lung disease phenotype of older bENaC-Tg mice also shows some differences compared to patients with CF, such as transient eosinophilic inflammation, in addition to chronic airway neutrophilia at juvenile ages, and clearance of spontaneous bacterial airway infection and development of pulmonary emphysema rather than bronchiectasis in adult mice [26,27,[30][31][32][33].…”

“…A series of studies in bENaC-Tg mice validated the concept that ASL depletion with hyperconcentrated mucus impairs mucociliary clearance, causes CF-like mucus plugging and sets the stage for chronic airway inflammation and bacterial infection [22]. Interestingly, recent studies in bENaC-Tg mice maintained under germ-free conditions demonstrated that mucus stasis per se is sufficient to cause airway inflammation, probably due to trapping of inhaled irritants that trigger the release of pro-inflammatory chemokines, such as keratinocyte chemoattractant and macrophage inflammatory protein-2, from airway epithelia and/or macrophages, even in the absence of bacterial infection [26]. Conversely, in the presence of bacteria in the environment, bENaC-Tg mice develop spontaneous airway infection in the neonatal period and show reduced clearance of CF-associated pathogens such as Pseudomonas aeruginosa and Haemophilus influenzae at older ages [17,26].…”

“…Interestingly, recent studies in bENaC-Tg mice maintained under germ-free conditions demonstrated that mucus stasis per se is sufficient to cause airway inflammation, probably due to trapping of inhaled irritants that trigger the release of pro-inflammatory chemokines, such as keratinocyte chemoattractant and macrophage inflammatory protein-2, from airway epithelia and/or macrophages, even in the absence of bacterial infection [26]. Conversely, in the presence of bacteria in the environment, bENaC-Tg mice develop spontaneous airway infection in the neonatal period and show reduced clearance of CF-associated pathogens such as Pseudomonas aeruginosa and Haemophilus influenzae at older ages [17,26]. Collectively, these studies demonstrated that this mouse model exhibits many characteristic features of early CF lung disease [27][28][29].…”