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Environmental tobacco smoke and newborn lung development

Institution: University of California, Davis
Investigator(s): Kent Pinkerton, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0327 Award: $440,500
Subject Area: General Biomedical Science
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Environmental tobacco smoke (ETS) is defined as the combination of sidestream smoke released from the burning end of a cigarette and that portion of mainstream smoke exhaled by smokers. Health effects associated with exposure to ETS have been clearly demonstrated, but still remain somewhat controversial. In 1993 the U.S. Environmental Protection Agency declared environmental tobacco smoke (ETS) to be a human carcinogen that kills approximately 3,000 nonsmokers a year. Young children are also affected by ETS exposure with increases in the incidence of pneumonia, bronchitis, and middle ear infection. For children with asthma, ETS exposure increases the severity and frequency of asthmatic attacks. However, the cause(s) for greater and more adverse health risks associated with ETS exposure in children compared with adults is (are) unknown.

We propose to study in our laboratory the effects of exposure to ETS on the maturation and function of the lung airways during fetal and early postnatal development in rats. This species is ideal to study due to its rapid fetal and postnatal growth to adulthood over a period of approximately 70 days. We have found that ETS exposure during the fetal and early postnatal periods is associated with a significant increase in lung airway narrowing, similar to that seen in asthmatic children. Also associated with these hyperactive airways is a dramatic increase in pulmonary neuroendocrine cells (PNECs), which compose a small fraction of the cells lining the lung airways. The function of PNECs is unknown; however, they are thought to be important in the pulmonary response to substances that are inhaled into the lungs and help to regulate airway tone and function.

It is our hypothesis that PNECs may be directly responsible for increased airway responsiveness (such as that seen in asthma) by either releasing bronchoconstrictive mediators or by increasing the mass of airway smooth muscle through smooth muscle cell proliferation. We propose to test this hypothesis in rats using environmental tobacco smoke (ETS) with exposure occurring during critical periods of lung growth and development from fetal to early adulthood in the rat. An important observation from our laboratory has been that when rats are exposed to ETS in utero (via the mother) followed by direct exposure for the first 3 weeks of life, their lungs remain markedly hyperresponsive when measured at 8 weeks of age, despite the absence of ETS exposure for the preceding 5 weeks. The discovery of this change in the lungs due to smoke exposure in newborn rats is highly analogous to the development of childhood asthma in humans. This animal model affords us the opportunity to examine whether there is a critical period during lung development when exposure to ETS leads to increased airway hyperresponsiveness and whether changes in airway PNEC number and/or function might be responsible for these observed changes.

Final Report
Childhood exposure to a variety of indoor air contaminants including environmental tobacco smoke, produces significant risks in asthma, airway hyperresponsiveness, and other respiratory symptoms such as cough, wheeze, and mucus production. However, the mechanisms leading to this process in the developing respiratory system are unknown. Through support from TRDRP, we have demonstrated that fetal and early postnatal exposure to environmental tobacco smoke are associated with a significant elevation in airway hyperreactivity and a dramatic increase in pulmonary neuroendocrine cells (PNECs), rare epithelial cells lining the lung airways. We hypothesized that PNECs may be directly responsible for increased airway responsiveness by either releasing bronchoconstrictive mediators or by increasing the mass of airway smooth muscle. We have tested this hypothesis in a rodent model using aged and diluted sidestream cigarette smoke (ADSS) as a surrogate for environmental tobacco smoke. We have documented profound increases in airway reactivity and the presence of increased numbers of PNECs in the lungs of young adult rats exposed to environmentally relevant concentrations of ADSS. These changes have been noted using a concentration of 1 mg/m3 of total suspended particulates (TSP) with in utero exposure to ADSS followed by 8 weeks of continued exposure during postnatal growth to young adulthood. These animals exhibited marked alterations in airway sensitivity and PNEC frequency in contrast to animals which had been exposed to ADSS only during the prenatal period or only to ADSS during the postnatal period, but not both. We hypothesized that these changes are due to ADSS exposure during critical windows of lung growth and development that include both fetal and early postnatal periods of life. We subsequently tested our hypothesis that early exposure to environmental tobacco smoke during the perinatal period is sufficient to produce a lasting response into adulthood by exposing timed pregnant dams to ADSS during gestation through the first three weeks of postnatal life. Following five weeks’ of recovery in filtered air, the lungs of these animals remained markedly hyperresponsive when measured at 8 weeks of age. This model is highly analogous to the development of childhood asthma in humans. Application of this model afforded us the opportunity to examine precise times that are critical during lung development when exposure to ADSS leads to increased airway responsiveness. This work has been extended to studies to examine alterations in adenyl cyclase levels. Such changes have been observed in humans associated with asthmatic-like conditions and may also provide new evidence for a potential mechanism leading to Sudden Infant Death Syndrome (SIDS).
Publications

Extended exposure to aged and diluted sidestream cigarette smoke (ADSS) alters pulmonary neuroendocrine cells (PNECS) in neonatal rats
Periodical: Toxicologist Index Medicus:
Authors: Avadhanam KP, Plopper CG, Pinkerton KE ABS
Yr: 1998 Vol: 42 Nbr: 1-S Abs: Pg: 1723

Exposure to the developing rat lung to environmental tobacco smoke induces expression of CYP1A1 mRNAbut not NADPH cytochrome P450 reductase
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Royce FH, Chan JO, Lee CH, Pinkerton KE ABS
Yr: 1998 Vol: 157 Nbr: 3 Abs: Pg: A13

Distribution of neuroepithelial bodies (NEBS) in whole mount rat airways - effects of exposure to aged and diluted sidestream cigarette smoke (ADSS)
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Avadhanam KP, Peake JL, Pinkerton KE ABS
Yr: 1998 Vol: 157 Nbr: 3 Abs: Pg: A157

Comparative biology of the lower respiratory tract: relevance to environmental air pollutants
Periodical: Toxicologist Index Medicus:
Authors: Pinkerton KE, Hyde DM, Evans MJ, Plopper CG ABS
Yr: 1998 Vol: 42 Nbr: 1-S Abs: Pg: 573

Species variability in the cellular and metabolic characteristics of the mammalian lung
Periodical: Toxicologist Index Medicus:
Authors: Plopper CG, Evans MJ, Pinkerton KE, Buckpitt AR ABS
Yr: 1998 Vol: 42 Nbr: 1-S Abs: Pg: 570

Site-selective differences in cytochrome P450 isoform activities. Comparison of expression in rat and rhesus monkey lung and induction in rats
Periodical: Drug Metabolism and Disposition Index Medicus:
Authors: Lee C, Watt KC, Chang AM, Plopper CG, Buckpitt AR, Pinkerton KE ART
Yr: 1998 Vol: 26 Nbr: Abs: Pg: 396-400

Maternal exposure to environmental tobacco smoke alters Clara cell secretory protein expression in fetal rat lung
Periodical: American Journal of Physiology Index Medicus:
Authors: Ji CM, Royce FH, Truong U, Plopper CG, Singh G, Pinkerton KE ART
Yr: 1998 Vol: 19 Nbr: Abs: Pg: L870-L876

Perinatal exposure to aged and diluted sidestream cigarette smoke produces airway hyperresponsiveness in older rats
Periodical: Toxicology and Applied Pharmacology Index Medicus:
Authors: Joad JP, Bric JM, Peake JL, Pinkerton KE ART
Yr: 1999 Vol: 155 Nbr: Abs: Pg: 253-260

Alteration of pulmonary neuroendocrine cells during epithelial repair of naphthalene-induced airway injury
Periodical: American Journal of Pathology Index Medicus:
Authors: Peake JL, Reynolds BR, Stripp BR, Stephens KE, Pinkerton KE ART
Yr: 2000 Vol: 156 Nbr: Abs: Pg: 279-286

Effect of in utero and postnatal exposure to environmental tobacco smoke on the developmental expression of pulmonary cytochrome P450 monooxygenases
Periodical: Journal of Biochemical and Molecular Toxicology Index Medicus:
Authors: Lee CZ, Royce FH, Denison MS, Pinkerton KE ART
Yr: 2000 Vol: 14 Nbr: Abs: Pg: 121-130

The mammalian respiratory system and critical windows of exposure for children's health
Periodical: Environmental Health Perspectives Index Medicus:
Authors: Pinkerton KE, Joad JP ART
Yr: 2000 Vol: 108 Nbr: 3 Abs: Pg: 457-462

Environmental tobacco smoke and perinatal airway remodeling
Periodical: Toxicologist Index Medicus:
Authors: Pinkerton KE, Avadhanam KP, Bric J, Kott K, Joad JP ABS
Yr: 1999 Vol: 48 Nbr: 1-S Abs: 783 Pg:

Exposure to environmental tobacco smoke increases the sensitivity of the lungs to ozone-induced injury
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yu M, Witschi HP, Pinkerton KE ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A24 Pg:

Effect of aged and diluted sidestream cigarette smoke (ADSS) on lung injury and repair in the adult mouse
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Brown CD, O'Donnell KJ, Pinkerton KE, Plopper CG ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A437 Pg:

Beta-naphthoflavone promotes CYP1A1 expression in the vascular endothelium but not in the respiratory epithelium of the prenatal rat lung
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Royce FH, Migliaccio CA, Peake JL, Albuquerque CA, Pinkerton KE ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A439 Pg:

Monocyte chemokine expression by airway epithelium is enhanced following exposure to environmental tobacco smoke
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Li C, Pinkerton KE, Hyde DM ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A510 Pg:

Environmental tobacco smoke (ETS) increases ozone-induced lung injury in a dose-dependent manner
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yu M, Witschi HP, Pinkerton KE ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A174 Pg:

Sidestream smoke exposure impairs lung repair from injury
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Evans MJ, Brown CD, et al ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A174 Pg:

Exposure to environmental tobacco smoke (ETS) enhances the sensitivity of the lungs to ozone-induced injury
Periodical: Toxicologist Index Medicus:
Authors: Pinkerton KE, Yu M, Witschi HP ABS
Yr: 2000 Vol: 54 Nbr: 1 Abs: 244 Pg:

The toxicology of environmental tobacco smoke.
Periodical: Annual Review of Pharmacology and Toxicology Index Medicus:
Authors: Witschi H, Joad JP, and Pinkerton KE ART
Yr: 1997 Vol: 37 Nbr: Abs: Pg: 29-52

Perinatal exposure to environmental tobacco smoke induces adenylyl cyclase and alters Perinatal exposure to environmental tobacco smoke induces adenylyl cyclase and alters receptor-mediated cell signaling in brain and heart of neonatal rats._x000d_
Periodical: Brain Research Index Medicus:
Authors: Slotkin TA, Pinkerton KE, Garofolo MC, Auman JT, McCook EC, and Seidler FJ ART
Yr: 2001 Vol: 898 Nbr: Abs: Pg: 73-81

Methacholine responsiveness of proximal and distal airways of monkeys and rats using videomicrometry.
Periodical: Journal of Applied Physiology Index Medicus:
Authors: Kott KS, Pinkerton K, Bric JM, Ploppper CG, Avadhanam KP, and Joad JP ART
Yr: 0 Vol: Nbr: Abs: Pg:

Short-term exposure to aged and diluted sidestream cigarette smoke enhances ozone-induced lung injury in B6C3F1 mice.
Periodical: Toxicological Sciences Index Medicus:
Authors: Yu M, Pinkerton KE, and Witschi H ART
Yr: 0 Vol: Nbr: Abs: Pg:

Extended exposure to aged and diluted sidestream cigarette smoke (ADSS) alters pulmonary neuroendocrine cells (PNECS) in neonatal rats.
Periodical: Toxicological Sciences Index Medicus:
Authors: Avadhanam KP, Plopper CG, and Pinkerton KE ART
Yr: 1998 Vol: 42 Nbr: I-S Abs: Pg: 350

Exposure of the developing rat lung to environmental tobacco smoke induces expression of CYP1A1 mRNA but not NADPH cytochrome P450 reductase.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Royce FH, Chan JO, Lee CH and Pinkerton KE ABS
Yr: 1998 Vol: 157 Nbr: 3 Abs: Pg: A13

Perinatal exposure to sidestream cigarette smoke (SS) produces airway hyperresponsiveness in older rats.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Joad JP, Bric KM and Pinkerton KE ART
Yr: 1998 Vol: 157 Nbr: 3 Abs: Pg: A697

Naphthoflavone promotes CYP1A1 expression in the vascular endothelium but not in the respiratory epithelium of the prenatal rat lung.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Royce FH, Migliaccio CA, Peake JL, Albuquerque CA, and Pinkerton KE ART
Yr: 1999 Vol: 159 Nbr: 3 Abs: Pg: A439

Effects of maternal exposure to naphthoflavone (BNF) on amniotic fluid volume and fetal lung development.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Albuquerque CA, Royce F, Stephens K, Gilbert W, and Pinkerton KE ART
Yr: 1999 Vol: 159 Nbr: 3 Abs: Pg: A669