FOXA2 depletion leads to mucus hypersecretion in canine airways with respiratory diseases

Abstract

Because of exposure to environmental pollutants, infectious agents, and genetic predisposition, companion animals develop respiratory illnesses similar to those in humans. Older dogs of smaller breeds develop canine infectious respiratory disease, chronic bronchitis, and chronic obstructive pulmonary disease, with chronic lung infection, airway goblet cell hyperplasia and metaplasia, and mucus hypersecretion. Excessive mucus clogs airways, reduces gas exchanges, disables the mucociliary clearance, and reduces drug penetration. The Forkhead box protein A2 (FOXA2) is a key transcriptional regulator that maintains airway mucus homeostasis. Prior studies have shown that FOXA2 expression is frequently depleted in diseased human airways. Unfortunately, FOXA2 depletion has not been examined in dogs. Our current study indicated that both single bacterial infection by Pseudomonas aeruginosa and Bordetella bronchiseptica and polymicrobial infection by viral/bacterial pathogens depleted FOXA2 in canine airways, resulting in goblet cell hyperplasia and metaplasia and excessive mucus production. Furthermore, P. aeruginosa virulence factor pyocyanin activated the antagonistic STAT6 and epidermal growth factor receptor signalling pathways to inhibit FOXA2. Unravelling the mechanism of FOXA2 inactivation will hasten the development of non-antibiotic therapeutics to improve mucociliary clearance of pathogens in canine airway.

Inactivation of FOXA2 by Respiratory Bacterial Pathogens and Dysregulation of Pulmonary Mucus Homeostasis

“…Interestingly, MUC5B gene transcription is differentiallyregulated by FOXA2. Inhibition of FOXA2 by bacterial pathogens elevates MUC5B expression (26,(52)(53)(54). In contrast, FOXA2 positively regulates MUC5B expression in both idiopathic pulmonary fibrosis (55) and asthma (56), most likely caused by polymorphism in the MUC5B promoter (57).…”

Molecular characterization of pulmonary defenses against bacterial invasion in allergic asthma: The role of Foxa2 in regulation of β-defensin 1

“…Foxa2 is highly conserved and widely expressed during murine embryogenesis and in adult tissues, where it functions as a primary transcription factor mediating the expression of genes involved in homeostasis and defenses, especially in the lung tissues [18]. Studies report decreased levels of Foxa2 in allergic diseases and asthma [20,24]. Therefore, genes associated with defenses may be affected by the depletion of Foxa2 in allergic diseases and asthma.…”

Pulmonary Mycosis Drives Forkhead Box Protein A2 Degradation and Mucus Hypersecretion through Activation of the Spleen Tyrosine Kinase–Epidermal Growth Factor Receptor–AKT/Extracellular Signal-Regulated Kinase 1/2 Signaling

“…Many clinical features of respiratory diseases in companion animals resemble human patients, including CB, COPD, goblet cell metaplasia and hyperplasia, mucus hypersecretion, and chronic lung infections. 35 The prevalence of blastomycosis and histoplasmosis in dogs and cats is comparable to humans. 48 Notably, geographic prevalence of canine pulmonary mycoses overlaps with that of humans, allowing it to be a potential epidemiologic marker to predict outbreaks in human.…”

“…29 Infections by respiratory bacterial pathogens Pseudomonas aeruginosa, Mycoplasma pneumoniae, and Bordetella bronchiseptica, as well as exposure to P. aeruginosa exotoxin pyocyanin consistently reduce the expression of FOXA2 in human, mouse, and canine airways. 28,30e34 FOXA2 is also depleted in human COPD lungs 34,35 and in canine patients with naturally developed COPD and CB. 35 Imbalance among cytokine responses often plays an important role in driving and worsening airway disease pathogenesis.…”

“…28,30e34 FOXA2 is also depleted in human COPD lungs 34,35 and in canine patients with naturally developed COPD and CB. 35 Imbalance among cytokine responses often plays an important role in driving and worsening airway disease pathogenesis. Type 1 T helper (Th1) cytokines, including interferon-g (IFN-g) and tumor necrosis factor-a/b (TNF-a/ b), elevate airway hyperresponsiveness and activate antigenpresenting cells, including macrophages.…”