Pulmonary neuroendocrine (PNECs) cells are widely distributed throughout the airway mucosa. These cells can be solitary or aggregated to form neuroepithelial bodies (NEBs), which are richly innervated by the vagus nerve. PNECs/NEBs are important for early phases of lung development and also associated with stem cell niches in the airways. They are airway sensors. Airway sensory receptors are biosensors that detect lung inflammation and injury through various mediators and cytokines. This information is transmitted through vagal afferents to the brain and produces a host of responses that regulate the pathophysiological process. Increasing evidence suggests that the vagus nerve plays an important role in a variety of pulmonary diseases from asthma, COPD, ARDS to lung cancer. Pulmonary fibrosis (PF) can result from a variety of insults to the lung. Lung repair following an insult-induced injury is a complex process involving both resident cells and recruited cells. The progression of PF results from a network of interactions among mediators, cytokines, and growth factors derived from inflammatory, endothelial, and epithelial cells, which leads to lung remodeling, deposition of collagen, limitation of gas exchange, and dyspnea. The vagus nerve is closely related to each component of this network, thus its function may influence the outcome of PF. Since lung injury is a major component in the development of PF and harmful insults to the lung may stimulate the NEB-Vagal System (NVS), a novel hypothesis that activation of the NVS promotes lung fibrosis will be tested. [If this hypothesis is correct, suppression of the NVS should attenuate fibrosis, whereas stimulation of the NVS should promote fibrosis. By examining lung fibrosis in bleomycin treated mice in which the NVS is either stimulated or suppressed (vagotomy, medication, gene manipulation, or cell adoptive transfer), and by assessing well-established cellular and molecular pathways that lead to PF with different techniques (histology, physiology, cytology and biochemistry), the underlying neural mechanisms will be delineated.] Successful completion of the studies will establish a novel neural mechanism in the pathogenesis of PF. [This potentially may lead to a new pharmacological approach to treat or to limit chronic fibrotic diseases in the Veteran population.]
Lung diseases are a major cause of illness and death in the Veteran population. Many of the diseases are related to lung fibrosis (LF), which is due to increased collagen and has no effective treatment. In the lung, there are specialized neuroendocrine cells connected to nerves, forming a neuroendocrine system (NS). The NS is essential for lung repair and influences progression of pulmonary diseases. We hypothesize that the NS promotes LF. We examined biochemistry, physiology and histology of both lungs in a mouse model for LF with one lung denervated and compared severity of the LP. Indeed, we found that a chemical released from the NS can promote LF. In this application, we will investigate the mechanism. Since pulmonary diseases related to LF form a major pulmonary patient population at VA hospitals, successful completion of the studies will establish a novel neural mechanism in the lung disease and may improve VA patient management.
