Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans. In many respects, the anatomy, biochemistry, physiology, size, and genetics of pigs resemble those of humans. Thus pigs with a targeted CFTR gene might provide a good model for CF. Here, we review aspects of porcine airways and lung that are relevant to CF.

Although destructive airways disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing Mucin 5B (MUC5B) and Mucin 5AC (MUC5AC) were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography (CT)-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared “permanent” since they did not dissolve in dilute BALF matrix, they could be solubilized by a novel reducing agent (P2062), but not N-acetylcysteine (NAC) or DNase. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytics and anti-inflammatory agents should be explored as preventive therapy.

Florida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine H 1 -and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, β-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction. Keywords bronchoconstriction; mucus transport; natural therapiesFlorida red tide is a harmful algal bloom caused by the dinoflagellate Karenia brevis (previously Gymnodinium breve). K. brevis produces at least nine structurally-related polyether brevetoxins (PbTxs) (1-3), with PbTx-2 and PbTx-3 being the predominant forms (4,5). As a ) is included in the provisional patent application filed on behalf of the University of North Carolina at Wilmington by aaiPharma; A.J.B. has provisional patents filed with respect to treatment of mucociliary diseases for synthetic and natural products derived from cultured red tide, and has an interest in any licensing that might arise from patents and final patents that are not filed yet and, thus, have not been thoroughly reviewed by the U.S. Patent and Copyright Office; J.R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.G.B. has provisional patents filed with respect to treatment of mucociliary diseases for synthetic and natural products derived from cultured red tide, and has an interest in any licensing that might arise from patents and final patents not filed yet and, thus, ...