Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma

Abstract

Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas β2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma.

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

“…In the current study, we have expanded upon those findings by demonstrating that cholinergic stimulation in the absence of an inciting insult is sufficient to evoke airway hyperreactivity. Moreover, while previous studies in mice suggest that repeated cholinergic stimulation exaggerates airway narrowing in lung slices ex vivo [18], our studies in the neonatal piglet suggest that repeated stimulation is not necessary to evoke airway pathophysiology.…”

Inhibiting Airway Smooth Muscle Contraction Using Pitavastatin: A Role for the Mevalonate Pathway in Regulating Cytoskeletal Proteins

“…Lung slices were obtained from wild-type C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME, USA) (Patel et al, 2017). Mice inhaled nebulized MCh (30 mg/ml) for 10 min followed by intratracheal (IT) treatment with either PEG400 (drug vehicle) or 5 mg/kg pitavastatin; treatments were repeated daily between postnatal day 15 and 20 (a total of 5 days).…”

Neurotrophins in Asthma

“…These findings emphasize early life as a critical time window for the susceptibility to asthma. Notably, NT4 −/− mice were protected from early life allergen-induced airway hyperinnervation, hypercontractility, and mucus overproduction, while having no change in airway inflammation [57••, 59]. Lineage tracing of TrkB in mice showed highly selective TrkB expression in nerves (Fig.…”

“…Therefore, elevated NT4 levels following early life allergen exposure likely through an indirect mode of action by causing airway dysfunction through aberrant neural innervation [58••]. Functional rescue assays in NT4 −/− mice identified that the hypercontractile phenotype of ASM is caused by cholinergic hyperinnervation, while deregulated neural control of GABA secretion from PNECs is involved in mucus overproduction following early life allergen exposure [40••, 59]. Consistent with the findings in the rodent model of early life allergen exposure, children with asthma have elevated serum levels of NT4 [56].…”