Air pollutants, genes and early childhood acute bronchitis.

BACKGROUND: Studies have reported gene-by-environment interaction for chronic respiratory conditions but none on acute illnesses in children. We investigated, longitudinally, whether genotype modifies the relationship of environmental exposures (second-hand tobacco smoke, polycyclic aromatic hydrocarbons, particulate matter <2.5µm (PM2.5)) with acute bronchitis in children below two years. METHODS: A random sample of 1133 children, born between 1994 and 1998, in two districts of the Czech Republic, was followed-up from birth, of which 793 were genotyped. Pediatric records were abstracted for respiratory illnesses. Second-hand tobacco smoke exposure from household members was obtained through questionnaires and verified using urine cotinine. Air monitoring provided estimates of ambient polycyclic aromatic hydrocarbons and PM2.5. Additionally, we collected information on a range of potential confounders including breastfeeding history, indoor fuel use, other children in household, maternal characteristics, ambient temperature etc. DNA was extracted from tissues taken from the middle of the placenta, opposite the umbilical cord. We examined six single nucleotide polymorphisms (GSTM1, GSTP1, GSTT1, CYP1A1 MspI, EPHX1 exon 3 and 4) and one (EPHX1) diplotype. To investigate effect measure modification we constructed logistic regression models using generalized estimating equations (for repeated observations) stratified by genotypes. RESULTS: The EPHX1 low activity diplotype consistently imparts greater susceptibility to bronchitis from second-hand tobacco smoke, polyclic aromatic hydrocarbons (PAH) and PM2.5. Each of these three classes of exposure also showed elevated risk for bronchitis in the presence of either one or two histidines at exon 3 and exon 4 of EPHX1. Additional effect modifiers include CYP1A1 and GSTT1. CONCLUSION: Several xenobiotic metabolizing genes may modify the impact of second-hand tobacco smoke and ambient air pollutants, polycyclic aromatic hydrocarbons and PM2.5, on acute bronchitis in preschool children.

Distinct tachykinin NK(1) receptor function in primate nucleus tractus solitarius neurons is dysregulated after second-hand tobacco smoke exposure.

BACKGROUND AND PURPOSE: Second-hand tobacco smoke (SHS) exposure in children increases the risk of asthma and sudden infant death syndrome. Epidemiological and experimental data have suggested SHS can alter neuroplasticity in the CNS, associated with substance P. We hypothesized that exposure to SHS in young primates changed the effect of substance P on the plasticity of neurons in the nucleus tractus solitarius (NTS), where airway sensory information is first processed in the CNS. EXPERIMENTAL APPROACH: Thirteen-month-old rhesus monkeys were exposed to filtered air (FA, n= 5) or SHS (n= 5) for >6 months from 50 days of their fetal age. Whole-cell patch-clamp recordings were performed on NTS neurons in brainstem slices from these animals to record the intrinsic cell excitability in the absence or presence of the NK(1) receptor antagonist, SR140333 (3 µM). KEY RESULTS: Neurons were electrophysiologically classified based on their spiking onset from a hyperpolarized membrane potential into two phenotypes: rapid-onset spiking (RS) and delayed-onset spiking (DS) types. In RS neurons, SR140333 reduced the spiking response, similarly in both FA- and SHS-exposed animals. In DS neurons, SR140333 almost abolished the spiking response in FA-exposed animals, but had no effect in SHS-exposed animals. CONCLUSIONS AND IMPLICATIONS: The contribution of NK(1) receptors to cell excitability depended on firing phenotype of primate NTS neurons and was disrupted by SHS exposure, specifically in DS neurons. Our findings reveal a novel NK(1) receptor function in the primate brainstem and support the hypothesis that chronic exposure to SHS in children causes tachykinin-related neuroplastic changes in the CNS.

Exposure to air pollution in critical prenatal time windows and IgE levels in newborns.

The objective of this study was to analyze the mechanisms by which exposure to ambient air pollutants influences respiratory health may include altered prenatal immune development. To analyze associations between elevated cord serum Immunoglobulin E (IgE) levels and maternal air pollution exposure during each month of gestation. Total cord serum IgE was determined by the CAP system and mothers' total IgE levels by nephelometry for 459 births in the Czech Republic from May 1994 to mid-January 1997. Concentrations of polycyclic aromatic hydrocarbons (PAHs) and particulate matter <2.5 microns in diameter (PM(2.5) ) were measured in ambient air, and arithmetic means were calculated for each gestational month. Log binomial regression models were used to estimate prevalence ratios (PR) for elevated cord serum IgE (≥0.9 IU/ml) adjusting for district of residence, year of birth, and in further models, for maternal IgE (a surrogate for atopy) and gestational season. Heterogeneity by maternal atopy status was evaluated for associations of air pollution and of cigarette smoke. In adjusted models, PAH and PM(2.5) exposures in the second month of gestation were each associated with a lower prevalence of elevated cord serum IgE. For an average increase of 100 ng/m(3) of PAHs, the PR was 0.69 (95% confidence interval (CI): 0.50, 0.95); for 25 µg/m(3) increase in PM(2.5) , the PR was 0.77 (95% CI: 0.55, 1.07). Conversely, exposures later in gestation were associated with a higher prevalence of elevated cord IgE: in the fifth month, the PR for PAH exposure was 1.64 (95% CI: 1.29, 2.08), while for PM(2.5) in the sixth month, it was 1.66 (95% CI: 1.30, 2.13). In analyses stratified by maternal atopy, air pollutants were associated with altered cord serum IgE only among neonates with non-atopic mothers. Similarly, an association of cigarette smoke with elevated cord serum IgE was found only in non-atopic mothers. PAHs and PM(2.5) , constituents of both ambient air pollution and cigarette smoke, appear to influence fetal immune development, particularly among infants whose mothers are not atopic.

House-dust mite allergen and ozone exposure decreases histamine H3 receptors in the brainstem respiratory nuclei.

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergen (HDMA)+O3 or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA+O3 exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA+O3 changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.

Issues and challenges of non-tenure-track research faculty: the UC Davis School of Medicine experience.

Nationally, medical schools are appointing growing numbers of research faculty into non-tenure-track positions, paralleling a similar trend in universities. The American Association of University Professors (AAUP) issued a statement expressing concern that the marked growth in non-tenure-track faculty can undermine educational quality, academic freedom, and collegiality. Like other medical schools, the UC Davis School of Medicine has had a rise in non-tenure-track faculty in order to enhance its research mission, in particular in the Salaried Adjunct faculty track (SalAdj). SalAdj faculty have more difficulty in achieving promotion, report inequitable treatment and less quality of life, have less opportunity to participate in governance, and feel second-class and insecure. These issues reflect those described by the AAUP. The authors describe the efforts at UC Davis to investigate and address these issues, implementation of a plan for improvement based on task force recommendations, and the lessons learned. Supporting transfer to faculty tracks in the academic senate, enhancing financial support, ensuring eligibility for internal grants, and equitable space assignments have contributed to an improved career path and more satisfaction among SalAdj faculty. Challenges in addressing these issues include limited availability of tenure-track positions, financial resources, adequate communication regarding change, and compliance with existing faculty search policies.

Secondhand smoke exposure alters K+ channel function and intrinsic cell excitability in a subset of second-order airway neurons in the nucleus tractus solitarius of young guinea pigs.

Extended exposure to secondhand smoke (SHS) in infants and young children increases the incidence of cough, wheeze, airway hyper-reactivity and the prevalence and earlier onset of asthma. The adverse effects may result from environmentally-induced plasticity in the neural network regulating cough and airway function. Using whole-cell patch-clamp recordings in brainstem slices containing anatomically identified second-order lung afferent neurons in the nucleus tractus solitarius (NTS), we determined the effects of extended SHS exposure in young guinea pigs for a duration equivalent to human childhood on the intrinsic excitability of NTS neurons. SHS exposure resulted in marked decreases in the intrinsic excitability of a subset of lung afferent second-order NTS neurons. The neurons exhibited a decreased spiking capacity, prolonged action potential duration, reduced afterhyperpolarization, decrease in peak and steady-state outward currents, and membrane depolarization. SHS exposure effects were mimicked by low concentrations of the K+ channel blockers 4-aminopyridine and/or tetraethyl ammonium. The data suggest that SHS exposure downregulates K+ channel function in a subset of NTS neurons, resulting in reduced cell excitability. The changes may help to explain the exaggerated neural reflex responses in children exposed to SHS.

Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.

Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS and bronchiolitis in infants and asthma in older children.

Generational forecasting in academic medicine: a unique method of planning for success in the next two decades.

Multigenerational teams are essential to the missions of academic health centers (AHCs). Generational forecasting using Strauss and Howe's predictive model, "the generational diagonal," can be useful for anticipating and addressing issues so that each generation is effective. Forecasts are based on the observation that cyclical historical events are experienced by all generations, but the response of each generation differs according to its phase of life and previous defining experiences. This article relates Strauss and Howe's generational forecasts to AHCs. Predicted issues such as work-life balance, indebtedness, and succession planning have existed previously, but they now have different causes or consequences because of the unique experiences and life stages of current generations. Efforts to address these issues at the authors' AHC include a work-life balance workgroup, expanded leave, and intramural grants.

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.

Five-fold increase in pediatric parapneumonic empyema since introduction of pneumococcal conjugate vaccine.

A retrospective review of medical records for all pediatric parapneumonic empyema (PPE) patients admitted to our hospital from 1996 to 2006 revealed that PPE increased 5-fold in the post-heptavalent pneumococcal conjugate vaccine (PCV7) period (2001-2005) relative to the pre-PCV7 period (1996-2000), from 13 cases to 65. Most of this increase was associated with culture-negative empyema, which accounted for 61% of all post-2000 cases; 19% was culture-positive pneumococcal empyema. Our analysis indicates that non-PCV7 serotypes became more prevalent at our institution after introduction of the vaccine.

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.

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.

Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates.

BACKGROUND: Epidemiologic studies associate environmental tobacco smoke (ETS) exposure with childhood asthma. OBJECTIVE: To investigate whether specific pathophysiological alterations that contribute to asthma development in human beings can be induced in infant monkeys after perinatal ETS exposure. METHODS: Rhesus macaque fetuses/infants were exposed to ETS at 1 mg/m(3) of total suspended particulate matter from 50 days gestational age to 2.5 months postnatal age. Inflammatory and neural responses to ETS exposure were measured in the infant monkeys. RESULTS: Perinatal ETS exposure could induce systemic and local responses, which include significant elevation of plasma levels of C5a and brain-derived neurotrophic factor, as well as significant increases in pulmonary expression of proinflammatory cytokine TNF-alpha and T(H)2 cytokine IL-5, chemokine monocyte chemoattractant protein 1, and the density of substance P-positive nerves along the bronchial epithelium. Perinatal ETS exposure also significantly increased the numbers of mast cells, eosinophils, monocytes, and lymphocytes in the lungs of infant monkeys. In addition, ex vivo measurements showed significantly increased levels of IL-4 and brain-derived neurotrophic factor in the culture supernatant of PBMCs. Interestingly, as an important component of cigarette smoke, LPS was detected in the plasma of infant monkeys subjected to perinatal exposure to ETS. In contrast, an inhibitory effect of perinatal ETS exposure was also observed, which is associated with decreased phagocytic activity of alveolar macrophages and a significantly decreased level of nerve growth factor in the bronchoalveolar lavage fluid. CONCLUSION: Perinatal ETS exposure can induce a T(H)2-biased inflammatory response and alter airway innervation in infant monkeys.

Effects of environmental tobacco smoke exposure on pulmonary immune response in infant monkeys.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) in early life has adverse effects on lung development and increases asthma incidence and susceptibility to infection. We have previously reported that perinatal and postnatal exposure to ETS in infant monkeys leads to an impaired T(H)1 immune response in peripheral blood. OBJECTIVE: Determine whether ETS exposure during the perinatal period alters pulmonary immune maturation in the neonatal lung. METHODS: Nonhuman primates were exposed to ETS from gestation day 50 to 13 months postnatal age (perinatal ETS) or from 6 to 13 months (postnatal ETS). Control animals were only exposed to filtered air. T(H)1 and T(H)2-related cytokines, chemokines, and their corresponding receptors as well as transcription factors were analyzed in lung tissues at 13 months. RESULTS: Animals exposed to ETS beginning in utero exhibited more profound alterations in T(H)1 factors compared with animals exposed to ETS beginning at 6 months postnatal age. In perinatal ETS-exposed monkeys, mRNA for IFN-gamma, IL-2, IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, IFN-gamma-inducible T-cell chemoattractant, CXC chemokine receptor 3, IL-12 bioactive p70 subunit, and T-bet were significantly downregulated, whereas in postnatal ETS-exposed monkeys, only IFN-gamma, CXC chemokine receptor 3, and IL-12p70 were significantly downregulated. ETS effects on T(H)2 factors were less apparent and more variable: mRNA for thymus and activation-regulated chemokine was increased, and IL-10 protein was reduced. CONCLUSIONS: Environmental tobacco smoke exposure during early life enhances a local T(H)2 immunity by impairing normal pulmonary T(H)1 immune maturation. This effect was greater in animals beginning ETS exposure in utero.

The effects of inhaled corticosteroids on intrinsic responsiveness and histology of airways from infant monkeys exposed to house dust mite allergen and ozone.

Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA)+ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA+ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.

Early childhood lower respiratory illness and air pollution.

BACKGROUND: Few studies of air pollutants address morbidity in preschool children. In this study we evaluated bronchitis in children from two Czech districts: Teplice, with high ambient air pollution, and Prachatice, characterized by lower exposures. OBJECTIVES: Our goal was to examine rates of lower respiratory illnesses in preschool children in relation to ambient particles and hydrocarbons. METHODS: Air monitoring for particulate matter < 2.5 microm in diameter (PM(2.5)) and polycyclic aromatic hydrocarbons (PAHs) was conducted daily, every third day, or every sixth day. Children born May 1994 through December 1998 were followed to 3 or 4.5 years of age to ascertain illness diagnoses. Mothers completed questionnaires at birth and at follow-up regarding demographic, lifestyle, reproductive, and home environmental factors. Longitudinal multivariate repeated-measures analysis was used to quantify rate ratios for bronchitis and for total lower respiratory illnesses in 1,133 children. RESULTS: After adjustment for season, temperature, and other covariates, bronchitis rates increased with rising pollutant concentrations. Below 2 years of age, increments in 30-day averages of 100 ng/m(3) PAHs and of 25 microg/m(3) PM(2.5) resulted in rate ratios (RRs) for bronchitis of 1.29 [95 % confidence interval (CI), 1.07-1.54] and 1.30 (95% CI, 1.08-1.58), respectively; from 2 to 4.5 years of age, these RRs were 1.56 (95% CI, 1.22-2.00) and 1.23 (95% CI, 0.94-1.62), respectively. CONCLUSION: Ambient PAHs and fine particles were associated with early-life susceptibility to bronchitis. Associations were stronger for longer pollutant-averaging periods and, among children > 2 years of age, for PAHs compared with fine particles. Preschool-age children may be particularly vulnerable to air pollution-induced illnesses.

Effects of environmental tobacco smoke on the developing immune system of infant monkeys.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is associated with an increased incidence of allergic and infectious diseases among children that is thought to be partly due to the immaturity of the immune system. OBJECTIVE: We sought to investigate the effects of ETS exposure on immune development during the first year of life in the nonhuman primate. METHODS: Fifteen neonatal rhesus monkeys studied to 13 months of postnatal age were randomized into 3 groups: (1) exposure to filtered air, (2) continuous ETS exposure beginning at gestation day 50 (perinatal ETS); and (3) exposure to ETS beginning at 6 months of age (6-month ETS). Complete blood counts, lymphocyte subsets, and mRNA levels of 12 cytokines in PBMCs were measured. RESULTS: Fetal/infant exposure to ETS altered the normal maturation of mRNA levels of IFN-gamma, IL-2, and IL-10, as well as the ratio of CD4 to CD8 lymphocytes, compared with filtered-air control levels. Blood lymphocyte subset distribution also significantly differed based on the onset of exposure to ETS. Subacute exposure to ETS for 2 weeks in 6-month-old infants was found to increase levels of peripheral blood neutrophils and IL-6 mRNA. CONCLUSIONS: Short-term exposure to ETS can induce an acute systemic inflammatory response in the neonatal nonhuman primate, and long-term exposure to ETS beginning in utero or at 6 months of postnatal age can significantly alter immune effectors. CLINICAL IMPLICATIONS: Normal immune system development is compromised by in utero and postnatal exposure to ETS and might contribute to ETS-related childhood diseases.

Asthma/allergic airways disease: does postnatal exposure to environmental toxicants promote airway pathobiology?

UNLABELLED: The recent, dramatic increase in the incidence of childhood asthma suggests a role for environmental contaminants in the promotion of interactions between allergens and the respiratory system of young children. To establish whether exposure to an environmental stressor, ozone (O3), and an allergen, house dust mite (HDMA), during early childhood promotes remodeling of the epithelial-mesenchymal trophic unit (EMTU) of the tracheobronchial airway wall by altering postnatal development, infant rhesus monkeys were exposed to cyclic episodes of filtered air (FA), HDMA, O3, or HDMA plus O3. The following alterations in the EMTU were found after exposure to HDMA, O3, or HDMA plus O3: (1) reduced airway number; (2) hyperplasia of bronchial epithelium; (3) increased mucous cells; (4) shifts in distal airway smooth muscle bundle orientation and abundance to favor hyperreactivity; (5) interrupted postnatal basement membrane zone differentiation; (6) modified epithelial nerve fiber distribution; and (7) reorganization of the airway vascular and immune system. CONCLUSIONS: cyclic challenge of infants to toxic stress during postnatal lung development modifies the EMTU. This exacerbates the allergen response to favor development of intermittent airway obstruction associated with wheeze. And, exposure of infants during early postnatal lung development initiates compromises in airway growth and development that persist or worsen as growth continues, even with cessation of exposure.

Air pollutants and cough.

Epidemiological studies have shown that exposure to air pollution is associated with respiratory symptoms and decreases in lung function. This paper reviews recent literature showing that exposure to particulate matter, irritant gases, environmental tobacco smoke (ETS), mixed pollutants, and molds is associated with an increase in cough and wheeze. Some pollutants, like particulate matter and mixed pollutants, appear to increase cough at least as much as wheeze. Others, like irritant gases, appear to increase wheeze more than cough. For ETS, exposure during childhood is associated with cough and wheeze in adulthood, suggesting that the pollutant permanently alters some important aspect of the lungs, immune system or nervous system. We have shown in animal studies that pollutants change the neural control of airways and cough. Second hand smoke (SHS) exposure lengthened stimulated apnoea, increased the number of stimulated coughs, and augmented the degree of stimulated bronchoconstriction. The mechanisms included enhanced reactivity of the peripheral sensory neurones and second-order neurones in the nucleus tractus solitarius (NTS). NTS effects were due to a substance P mechanism at least in part. Ozone and allergen increased the intrinsic excitability of second-order neurones in the NTS. The animal studies suggest that the cough and wheeze experienced by humans exposed to pollutants may involve plasticity in the nervous system.

Environmental tobacco smoke suppresses nuclear factor-kappaB signaling to increase apoptosis in infant monkey lungs.

RATIONALE: Exposure to environmental tobacco smoke in early life has adverse effects on lung development. Apoptosis plays an essential role in development; however, the molecular mechanisms of pulmonary apoptosis induced by environmental tobacco smoke is unknown. OBJECTIVES: To investigate the mechanistic role of nuclear factor (NF)-kappaB, a critical cell survival pathway, in the developing lungs exposed to environmental tobacco smoke. METHODS: Timed-pregnant rhesus monkeys and their offspring were exposed to filtered air or to aged and diluted sidestream cigarette smoke as a surrogate to environmental tobacco smoke (a total suspended particulate concentration of 0.99 mg/m(3) for 6 h/d, 5 d/wk) from 45-50 d gestational age to 72-77 d postnatal age (n = 4/group). MEASUREMENTS AND MAIN RESULTS: NF-kappaB-DNA binding activity, regulated anti-apoptotic genes, and apoptosis were measured in lung tissues. Exposure to environmental tobacco smoke significantly suppressed NF-kappaB activation pathway and activity. Environmental tobacco smoke further down-regulated NF-kappaB-dependent anti-apoptotic genes and induced activation of caspases, cleavage of cellular death substrates (poly(ADP)-ribose polymerase and caspase-activated DNase) and an increase in the rate of apoptosis in the lung parenchyma. No significant alterations were observed for activator protein 1, p53 or Akt activity. CONCLUSIONS: Our results indicate that exposure to low levels of environmental tobacco smoke during a critical window of maturation in the neonatal nonhuman primate may compromise lung development with potential implications for future lung growth and function. These findings support our hypothesis that NF-kappaB plays a key role in the regulation of the apoptotic process.