Neural regulation of the pulmonary neuroendocrine system induce mucus overproduction
Barrios, Juliana Beverly
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The major goal of my study is to understand how the nervous system regulates lung function and disease pathophysiology. Asthma, which is a chronic allergic disease in the lung, has been associated with deregulated airway innervation. The two cell types in the lung that are innervated are airway smooth muscle cells and pulmonary neuroendocrine cells (PNECs). Given that asthma often starts in early childhood, prior research established a neonatal mouse model of allergen exposure to facilitate functional studies of nerves in the development of asthma. Our previous findings showed that allergen exposure to developing, postnatal lungs upregulated levels of neurotrophin 4 (NT4), and caused airway hyperinnervation associated with persistent mucus overproduction. In this work, I describe a novel role of the pulmonary neuroendocrine system in promoting mucus overproduction in early life through deregulated GABAergic signaling. PNECs are the only innervated epithelial cells and express a variety of neuropeptides and bioactive amines. However, how neural innervation affects PNEC secretion and function in disease is not known. Here, I demonstrated that PNECs were the only source of gamma-Aminobutyric acid (GABA) in airways and that GABA hypersecretion from PNECs was required for mucus overproduction following early life allergen exposure. Further, mice lacking NT4 were protected from allergen-induced PNEC hyperinnervation, GABA hypersecretion, and thus mucus overproduction, all which could be rescued with addition of GABA. These findings link PNECs and allergen-induced mucus overproduction through NT4-dependent innervation. Notably, like mice, infant nonhuman primates exhibit PNEC hyperinnervation following early life exposure to ozone and allergens. In addition, I demonstrate that GABA acts in concert with interleukin-13 to induce the proliferation of mucus-producing goblet cells in human airway epithelium cell cultures. Lastly, building upon our previous observations that mast cells contributed to the elevated NT4 levels after allergen exposure, I initiated a research project that investigates the function of a discrete, resident mast cell in: NT4 expression, PNEC innervation, and mucus overproduction. Together, my findings address a novel fundamental role of the neuroendocrine system biology in animal models of asthma. Targeting the nerve–PNEC axis may be a valid treatment strategy for mucus overproduction in asthma.