Innervation defects as a mechanism of childhood asthma
Aven, Linh Ma
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Currently, asthma affects 25.7 million people in the United States and is increasing in prevalence worldwide, with young children at high risk. Recent studies show that early environmental exposure can lead to asthma and impair lung function. While the development of asthma is not fully understood, findings indicate that cigarette smoke, ozone, allergen, or viral exposure to an immature lung can induce changes in airway innervation. However, the mechanisms underlying these changes and how these changes affect lung function are unknown. Normally, lung innervation plays a role in coughing, sensing, and breathing. We found that embryonic lung innervation requires brain-derived neurotrophin factor (BDNF) signaling and postnatal lung innervation requires neurotrophin 4 (NT4) signaling. Since both of these neurotrophins signal through tyrosine kinase receptor B (TrkB), they have temporally distinct roles in airway smooth muscle (ASM) innervation. We show that neurotrophins are released from ASM and act as target-derived signals for ASM innervation. We also show that early allergen exposure in neonatal mice increase NT4/TrkB signaling leading to ASM hyper-innervation. Notably, genetic disruption and small molecule blockade of NT4/TrkB signaling in early allergen exposed neonates prevented both acute and persistent airway hyper-reactivity without affecting baseline airway function or inflammation. Furthermore, biophysical assays using lung slices and isolated ASM cells demonstrated that NT4 was required for ASM hyper-contractility induced by early-life allergen exposure. Together, our findings show that the NT4/TrkB dependent increase in innervation plays a critical role in altering the ASM phenotype during postnatal growth, thereby linking early-life allergen exposure to persistent airway dysfunction. Our findings may explain why children who are exposed to environmental insults often develop asthma later in life. Findings from this study may also provide new pathways and targets for novel allergic asthma therapies.
Thesis (Ph.D.)--Boston University