John M. Bric

Extended secondhand tobacco smoke exposure induces plasticity in nucleus tractus solitarius second-order lung afferent neurons in young guinea pigs

Infants and young children experiencing extended exposure to secondhand smoke (SHS) have an increased occurrence of asthma, as well as increased cough, wheeze, mucus production and airway hyper‐reactivity. Plasticity in lung reflex pathways has been implicated in causing these symptoms, as have changes in substance P‐related mechanisms. Using whole‐cell voltage‐clamp recordings and immunohistochemistry in brainstem slices containing anatomically identified second‐order lung afferent nucleus tractus solitarius (NTS) neurons, we determined whether extended SHS exposure during the equivalent period of human childhood modified evoked or spontaneous excitatory synaptic transmission, and whether those modifications were altered by endogenous substance P. SHS exposure enhanced evoked synaptic transmission between sensory afferents and the NTS second‐order neurons by eliminating synaptic depression of evoked excitatory postsynaptic currents (eEPSCs), an effect reversed by the neurokinin‐1‐receptor antagonist (SR140333). The recruitment of substance P in enhancing evoked synaptic transmission was further supported by an increased number of substance P‐expressing lung afferent central terminals synapsing onto the second‐order lung afferent neurons. SHS exposure did not change background spontaneous EPSCs. The data suggest that substance P in the NTS augments evoked synaptic transmission of lung sensory input following extended exposure to a pollutant. The mechanism may help to explain some of the exaggerated respiratory responses of children exposed to SHS.

Effect of secondhand cigarette smoke, RSV bronchiolitis and parental asthma on urinary cysteinyl LTE4

Cysteinyl leukotrienes promote airway inflammation, bronchoconstriction and mucus hypersecretion. Cigarette smoking and respiratory syncytial virus (RSV) bronchiolitis are known to increase urinary cysteinyl leukotriene E4 (uLTE4), the end product of the cysteinyl leukotriene biosynthetic pathway. We tested the following hypotheses: (1) Secondhand smoke (SHS) exposure increases uLTE4 in well infants and in those hospitalized for RSV bronchiolitis; (2) Length of hospital stay for those with RSV bronchiolitis correlates with uLTE4; and (3) Infants with parent(s) with asthma will have higher uLTE4. Parental asthma for infants hospitalized with RSV bronchiolitis (n = 79) and Well babies (n = 31) was determined by questionnaire. Urine was analyzed for LTE4, cotinine, and creatinine. SHS exposure was determined by cotinine to creatinine ratio. Chi square, or t‐tests were used to determine significant differences between two groups. A three‐way analysis of variance compared the effects of SHS exposure and parental asthma on uLTE4 in Well versus RSV babies. Independent variables predicting length of hospital stay were determined by stepwise multiple regression. High SHS exposure and RSV significantly increased uLTE4. The SHS induced increase in uLTE4 was seen in infants with no parental asthma but not in those with parental asthma. Length of hospital stay positively correlated with uLTE4. We concluded that SHS exposure may increase the severity of bronchiolitis in RSV‐infected infants by enhancing production of cysLTs in infants with no parental asthma. Pediatr Pulmonol. 2008; 43:760–766.

Effect of Perinatal secondhand tobacco smoke exposure on in vivo and intrinsic airway structure/function in non-human primates

Infants exposed to second hand smoke (SHS) experience more problems with wheezing. This study was designed to determine if perinatal SHS exposure increases intrinsic and/or in vivo airway responsiveness to methacholine and whether potential structural/cellular alterations in the airway might explain the change in responsiveness. Pregnant rhesus monkeys were exposed to filtered air (FA) or SHS (1 mg/m(3) total suspended particulates) for 6 h/day, 5 days/week starting at 50 days gestational age. The mother/infant pairs continued the SHS exposures postnatally. At 3 months of age each infant: 1) had in vivo lung function measurements in response to inhaled methacholine, or 2) the right accessory lobe filled with agarose, precision-cut to 600 mum slices, and bathed in increasing concentrations of methacholine. The lumenal area of the central airway was determined using videomicrometry followed by fixation and histology with morphometry. In vivo tests showed that perinatal SHS increases baseline respiratory rate and decreases responsiveness to methacholine. Perinatal SHS did not alter intrinsic airway responsiveness in the bronchi. However in respiratory bronchioles, SHS exposure increased airway responsiveness at lower methacholine concentrations but decreased it at higher concentrations. Perinatal SHS did not change eosinophil profiles, epithelial volume, smooth muscle volume, or mucin volume. However it did increase the number of alveolar attachments in bronchi and respiratory bronchioles. In general, as mucin increased, airway responsiveness decreased. We conclude that perinatal SHS exposure alters in vivo and intrinsic airway responsiveness, and alveolar attachments.

Effects of extended sidestream smoke exposure on components of the C-fiber axon reflex

We have previously shown that young guinea pigs repeatedly exposed to sidestream cigarette smoke (SS) develop decreased airway reactivity of the C-fiber system without changing reactivity to one of its neurotransmitters, substance P (SP). This study was designed to determine whether the decreased reactivity was due to decreased responsiveness to another neurotransmitter, neurokinin A (NKA), decreased lung SP content, decreased affinity or number of NK1 receptors, and/or decreased number of C-fibers. Duncan Hartley guinea pigs were exposed to filtered air (FA) or to SS for 6 h/day, 5 days/week for 5 weeks starting at 1 week of age. SS exposure did not change, (1) airway reactivity to NKA injected into the pulmonary artery of their isolated perfused lungs (n = 6-7 each group), (2) lung SP content as measured by enzyme immunoassay (n = 12 each group), (3) NK1 receptor number or affinity as measured by radioligand binding (n = 7 each group), or (4) SP-immunoreactive nerve profiles of the terminal bronchioles or small airways (n = 6 each group). Thus, SS exposure does not decrease C-fiber system by reducing NKA responsiveness, decreasing SP content, changing NK1 receptors, or decreasing the number of C-fibers.