Wu ZX, Benders KB, Hunter DD, Dey RD. Early postnatal exposure of mice to side-steam tobacco smoke increases neuropeptide Y in lung. Am J Physiol Lung Cell Mol Physiol 302: L152-L159, 2012. First published October, 14, 2011 doi:10.1152/ajplung.00071.2011.-Our recent study showed that prenatal and early postnatal exposure of mice to sidesteam tobacco smoke (SS), a surrogate to environmental tobacco smoke (ETS), leads to increased airway responsiveness and sensory innervation later in life. However, the underlying mechanism initiated in early life that affects airway responses later in life remains undefined. The concomitant increase in nerve growth factor (NGF) after exposures suggests that NGF may be involved the regulation of airway innervation. Since NGF regulates sympathetic nerve responses, as well as sensory nerves, we extended previous studies by examining neuropeptide Y (NPY), a neuropeptide associated with sympathetic nerves. Different age groups of mice, postnatal day (PD) 2 and PD21, were exposed to either SS or filtered air (FA) for 10 consecutive days. The level of NPY protein in lung and the density of NPY nerve fibers in tracheal smooth muscle were significantly increased in the PD2-11SS exposure group compared with PD2-11FA exposure. At the same time, the level of NGF in lung tissue was significantly elevated in the PD2-11SS exposure groups. However, neither NPY (protein or nerves) nor NGF levels were significantly altered in PD21-30SS exposure group compared with the PD21-30FA exposure group. Furthermore, pretreatment with NGF antibody or K252a, which inhibits a key enzyme (tyrosine kinase) in the transduction pathway for NGF receptor binding, significantly diminished SS-enhanced NPY tracheal smooth muscle innervation and the increase in methacholine-induced airway resistance. These findings show that SS exposure in early life increases NPY tracheal innervation and alters pulmonary function and that these changes are mediated through the NGF. airway innervation; asthma; secondhand smoke; neurotrophic factor ENVIRONMENTAL TOBACCO SMOKE (ETS) is an environmental trigger factor that leads to airway inflammation and asthma symptoms in susceptible individuals and animals (25,33,34). Exposure to ETS in utero or during early postnatal development increases the incidence of respiratory illnesses (11,13,28,31,35) later in life. Epidemiological studies (11,13,25,28,(32)(33)(34)(35) show that the probability of developing or exacerbating childhood asthma increases in children of mothers who smoke cigarettes. These results suggest that the prenatal and early postnatal periods are critical periods of developmental sensitivity to cigarette smoke exposure. Indeed, our recent study (40) showed that exposure to side-steam tobacco smoke (SS) during prenatal and early postnatal life produces changes in lung function and airway innervation later in life, supporting the concept of an early life critical period of susceptibility. However, the underlying mechanism initiated by early life exposures that affect lung st...