Lung Growth In Children Research Articles

Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease-Associated Pulmonary Hypertension.

BackgroundEndostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH.Methods and ResultsSerum endostatin was measured in cross‐sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH‐CHD, N=185). Outcomes, assessed by regression and Kaplan‐Meier analysis, included hemodynamics, change in endostatin over time, and transplant‐free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH‐CHD. In APAH‐CHD, endostatin was associated with a shorter 6‐minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant‐free survival. Addition of endostatin to an NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells.ConclusionsEndostatin is associated with disease severity, disease improvement, and worse survival in APAH‐CHD. Endostatin with NT‐proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH‐CHD.

Abstract 14979: Endostatin as a Predictor of Severity and Survival in Pediatric Congenital Heart Disease Associated Pulmonary Hypertension

Introduction: Pediatric pulmonary arterial hypertension (PAH) is a multifactorial pulmonary vascular disease with high mortality. Endostatin (ES), an angiogenic inhibitor, is associated with disease severity and mortality in adults with PAH and poor lung growth in children. Hypothesis: Increased ES is associated with worse disease severity and outcomes in pediatric PAH. Methods: Serum ES levels were measured in two cohorts of pediatric PAH (IPAH, FPAH and APAH) patients; the cross-sectional CCHMC PAH Biobank (PAHB, N=175) and a longitudinal cohort from Children’s Hospital of Colorado (CHC, N=61). Outcomes included medical therapy, functional and hemodynamic measures, and survival (death, transplant, palliative shunt). Adjusted logistic and linear regressions and Kaplan-Meier analysis were used to assess the relationship between ES and clinical outcomes. Results: In both cohorts, ES was significantly higher in PAH associated with congenital heart disease (APAH-CHD, PAHB n=70, p=0.002; CHC n=29, p=0.007) and was highest in those with a ventricular shunt (n=24, p=0.001). In APAH-CHD, ES was associated with a decreased 6MWD (-108m, -187- -30, p=0.01) and increased mean right atrial pressure (mRAP 1.8mmHg, 0.3-3.3, p=0.02). Longitudinally, in the APAH-CHD subgroup when adjusted for age, sex, and multiple time points, higher ES was associated with increased PVRi and mPAP (PVRi 2.5WU*m 2 , 0.7-4.3, p=0.007; mPAP 10mmHg, 4.5-15, p<0.001). Kaplan-Meier analysis (Figure 1) demonstrated that ES was associated with worse outcomes in both cohorts, with an adjusted Cox proportional hazard ratio of 4.3 (1.13-16, p=0.03) in the PAHB. Conclusions: ES was associated with worse functional measures, pulmonary vascular hemodynamics, and survival in pediatric APAH-CHD. These observations suggest that serum ES could act as a pulmonary vascular specific biomarker to identify those who are at increased risk of developing PAH and predict poor outcomes in APAH-CHD.

What does calculating impacts of specific morbidity outcomes add to perceptions of air pollution health impact assessment?

Introduction: Health impact assessments often use broad categories of outcomes, e.g. all respiratory or all cardiovascular admissions. This minimises diagnostic misclassification but does not fully communicate the evidence on associations between air pollution and specific diseases. More specific health impact calculations may resonate with the public more than severe but rarer outcomes.Methods: Literature searches were done for meta-analyses pooling evidence on a variety of pollutants (PM10, PM2.5, NO2 and O3) and 40 health outcomes. We investigated the effects of short- and long-term exposure to pollution and did final calculations on 17 morbidity outcomes, rejecting those with weaker evidence, lack of baseline rates, and no priority from focus groups. The selected concentration-response functions were combined with monitoring site, baseline rate/cases and population (e.g. beside roads) data to calculate health impacts in up to 4 scenarios (roadside vs background (daily and annual); 75th vs 25th percentile daily average and a 20% reduction in annual average) across 9 UK and 4 Polish cities. The largest result per pollutant was given rather than summing across pollutants.Results: The largest change in number of cases was for children with low lung function in London (7927 for a 20% reduction in NO2). Changes in cases of acute bronchitis in children in London were also high (3683 for a 20% reduction in PM10). Warsaw had greater impacts on cardiovascular than respiratory endpoints compared with London. Other example statements include ‘living near busy roads in Oxford may stunt lung growth in children by 14%’ and ‘in London on higher pollution days, 142 more children with asthma experience symptoms than on lower pollution days’.Conclusions: Health impact statements for a wider variety of outcomes may aid communication of the importance of different health effects to policymakers and the public.

Discussing the impact of air pollution on heart disease

Discussing the impact of air pollution on heart disease

Stepwise management of asthma.

Stepwise management of asthma remains an area of evolving research. Asthma is one of the most expensive chronic diseases in the United States; stepwise management is an important area of focus, with several recent guidelines recommending management. This is a review of published English language literature, focusing on management guidelines for asthma in adult and pediatric patients. Asthma is a chronic disease whose assessment of severity allows for therapeutic goals to match the impairment noted. Good evidence exists to aid risk reduction, leading to decreased emergency room visits, preventing loss of lung function in adults and lung growth in children, and optimizing pharmacotherapy with reduced side effects profile. Recent asthma management guidelines incorporate 4 components of asthma care including: monitoring of severity, patient education, controlling external triggers, and medications, including recent attention to medication adherence. Asthma is an expensive chronic disease with preventive measures leading to reduced healthcare costs. Future targeted cytokine therapy to decrease serum and blood eosinophils may become an integral part of asthma management.

Ozone Exposure Alters Serotonin and Serotonin Receptor Expression in the Developing Lung

Ozone, a pervasive environmental pollutant, adversely affects functional lung growth in children. Animal studies demonstrate that altered lung development is associated with modified signaling within the airway epithelial mesenchymal trophic unit, including mediators that can change nerve growth. We hypothesized that ozone exposure alters the normal pattern of serotonin, its transporter (5-HTT), and two key receptors (5-HT2A and 5-HT4), a pathway involved in postnatal airway neural, epithelial, and immune processes. We exposed monkeys to acute or episodic ozone during the first 2 or 6 months of life. There were three exposure groups/age: (1) filtered air, (2) acute ozone challenge, and (3) episodic ozone + acute ozone challenge. Lungs were prepared for compartment-specific qRT-PCR, immunohistochemistry, and stereology. Airway epithelial serotonin immunopositive staining increased in all exposure groups with the most prominent in 2-month midlevel and 6-month distal airways. Gene expression of 5-HTT, 5-HT2AR, and 5-HT4R increased in an age-dependent manner. Overall expression was greater in distal compared with midlevel airways. Ozone exposure disrupted both 5-HT2AR and 5-HT4R protein expression in airways and enhanced immunopositive staining for 5-HT2AR (2 months) and 5-HT4R (6 months) on smooth muscle. Ozone exposure increases serotonin in airway epithelium regardless of airway level, age, and exposure history and changes the spatial pattern of serotonin receptor protein (5-HT2A and 5-HT4) and 5-HTT gene expression depending on compartment, age, and exposure history. Understanding how serotonin modulates components of reversible airway obstruction exacerbated by ozone exposure sets the foundation for developing clinically relevant therapies for airway disease.

WHO universal definition of severe asthma

In 2009, an expert panel met to propose a WHO definition of asthma severity and control, and criteria for describing exacerbations and their severity, which would be globally applicable. This review addresses their findings in the context of recent literature, and assesses the usefulness of these definitions in children in particular. Severe asthma was defined by the level of current clinical control and risks as: 'Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'. Severe asthma includes three groups, with different public health messages and challenges: untreated severe asthma, due to undiagnosed asthma or unavailability of therapy, difficult-to-treat severe asthma (due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or co-morbidity), and treatment-resistant severe asthma, including asthma for which control is not achieved despite the highest level of recommended treatment or asthma which is controlled only with the highest level of recommended treatment. These definitions will enable more precise measurement of the burden of severe childhood asthma globally. International collaborations in epidemiological and mechanistic studies, and randomized controlled trials of treatment, will be facilitated. However, both pathophysiology and severity are influenced by a number of factors with wide global variation; international comparisons should be interpreted with caution.

Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.

Effect of Breastfeeding on Lung Function in Childhood and Modulation by Maternal Asthma and Atopy

Guilbert TW, Stern DA, Morgan WJ, Martinez FD, Wright AL. Am J Respir Crit Care Med. 2007;176(9):843–848 PURPOSE OF THE STUDY. Breastfeeding and its relationship to the development of subsequent asthma remain controversial. To clarify these complex issues, this study examined the association between lung function and infant-feeding practices. STUDY POPULATION. A population-based cohort of healthy infants was enrolled at birth in the Children's Respiratory Study in Tucson, Arizona (n = 1246); the analysis was of 679 study participants on whom lung-function testing was performed at ages 11 and/or 16 years and provided data regarding infant-feeding practices. METHODS. In the Children's Respiratory Study in Tucson, feeding practices were assessed prospectively on the basis of questionnaires completed at enrollment and well-child visits. Formula introduction was categorized as having occurred before 2 months (n = 143, “early formula introduction”), from 2 to before 4 months (n = 336), or at ≥4 months (n = 200, “longer breastfed”). Lung function was measured at ages 11 and 16 years. A random-effects model was used to assess the relationship of infant-feeding practices to measures of lung function. RESULTS. Forced vital capacity (FVC) by age 16 was increased by 103 ± 40 mL (P = .01), and the forced expiratory volume in 1 second (FEV1)/FVC ratio was lower (−1.9 ± 0.6%; P = .004) in the longer-breastfed children compared with children with early formula introduction. This effect was modified after stratifying according to maternal asthma. Compared with children with early formula introduction, longer-breastfed children with asthmatic mothers had an FVC that was not increased (P = .7) and an FEV1/FVC ratio (−5.7 ± 2.4%; P = .02) that was significantly decreased by age 16. Longer-breastfed children with nonatopic, nonasthmatic mothers demonstrated an increased FVC (142 ± 71 mL; P = .047) and no decrease in FEV1/FVC (P = .7) compared with children with early formula introduction. CONCLUSIONS. Longer duration of breastfeeding favorably influences lung growth in children. However, in the presence of maternal asthma, longer breastfeeding is associated with decreased airflows. REVIEWER COMMENTS. There seems to be a differential effect of the relation of breastfeeding to lung function on the basis of the asthmatic background of the mother. Breastfed children with nonatopic, nonasthmatic mothers had an increased FVC and no decrease in their airflows. However, children of mothers with asthma with longer breastfeeding did not demonstrate any improvement in FVC but had a significant reduction in airflows, suggesting that the risk for increased asthma in this group may be partly a result of altered lung growth. Children with longer breastfeeding who had atopic but nonasthmatic mothers had intermediate findings, and they showed a similar increase in FVC compared with those with nonatopic, nonasthmatic mothers but a decrease in airflows similar to children with asthmatic mothers. These findings may support the speculation that the milk of mothers with atopy or asthma may differ with regard to immunologically active substances; thus, breastfeeding in these groups may have a different effect on growth and/or development of the airways. It goes without saying that the clinical significance of these findings is unknown. Human milk is uniquely suited to the feeding of infants. There are many well-documented benefits of breastfeeding. For children of nonasthmatic mothers, this study demonstrates a further benefit of breastfeeding. Additional study is needed draw firm conclusions for other infants.

Effect of Breastfeeding on Lung Function in Childhood and Modulation by Maternal Asthma and Atopy

The protective effect of breastfeeding on early respiratory infections is well established, but its relationship to the development of subsequent asthma remains controversial. To clarify these complex issues, we examined the association between lung function and infant-feeding practices. In the Tucson Children's Respiratory Study, feeding practices were assessed prospectively based on questionnaires completed at enrollment and well-child visits. Formula introduction was categorized as having occurred before 2 months (n = 143, "early formula introduction"), from 2 and before 4 months (n = 336), or at 4 months and older (n = 200, "longer breastfed"). Lung function was measured at age 11 and 16 years. A random-effects model was used to assess the relationship of infant-feeding practices to measures of lung function. FVC by age 16 was increased by 103 +/- 40.0 ml (P = 0.01), and the FEV1/FVC ratio was lower (-1.9 +/- 0.6%, P = 0.004) in the longer breastfed children compared with children with early formula introduction. This effect was modified after stratifying by maternal asthma. Compared with children with early formula introduction, longer breastfed children with asthmatic mothers had an FVC that was not increased (P = 0.7) and an FEV1/FVC ratio (-5.7 +/- 2.4%, P = 0.02) that was significantly decreased by age 16. Longer breastfed children with nonatopic, nonasthmatic mothers demonstrated an increased FVC (142 +/- 71.1 ml, P = 0.047) and no decrease in FEV1/FVC (P = 0.7) compared with children with early formula introduction. Longer duration of breastfeeding favorably influences lung growth in children. However, in the presence of maternal asthma, longer breastfeeding is associated with decreased airflows.

Exposure to Secondhand Smoke Among Students Aged 13-15 Years—Worldwide, 2000-2007

Breathing secondhand smoke (SHS) causes heart disease and lung cancer in adults and increased risks for sudden infant death syndrome, acute respiratory infections, middle-ear disease, worsened asthma, respiratory symptoms, and slowed lung growth in children. No risk-free level of exposure to SHS exists. The Global Youth Tobacco Survey (GYTS), initiated in 1999 by the World Health Organization (WHO), the Canadian Public Health Association, and CDC includes questions related to tobacco use, including exposure to SHS. This report examines data collected from 137 jurisdictions (i.e., countries and territories) during 2000-2007, presents estimates of exposure to SHS at home and in places other than the home among students aged 13-15 years who had never smoked, and examines the association between exposure to SHS and susceptibility to initiating smoking. GYTS data indicated that nearly half of never smokers were exposed to SHS at home (46.8%), and a similar percentage were exposed in places other than the home (47.8%). Never smokers exposed to SHS at home were 1.4-2.1 times more likely to be susceptible to initiating smoking than those not exposed. Students exposed to SHS in places other than the home were 1.3-1.8 times more likely to be susceptible to initiating smoking than those not exposed. As part of their comprehensive tobacco-control programs, countries should take measures to create smoke-free environments in all indoor public places and workplaces.

Mild to moderate asthma affects lung growth in children and adolescents

The effect of childhood asthma on lung growth is unclear. To show the effect of mild to moderate childhood asthma on lung growth. A total of 1041 children with mild to moderate asthma from the Childhood Asthma Management Program (CAMP) were compared with 5415 children without asthma from the Harvard Six Cities Study (H6CS). Sex-age-specific comparisons of lung growth in CAMP with the H6CS were made by using repeated-measures multiple linear regression models. Sex-age-specific percentages of children with asthma with abnormal (<5th percentile of H6CS) pulmonary function values were calculated. In both boys and girls, the ratio of FEV(1) to forced vital capacity (FVC) was significantly lower for children with than without asthma (P < .001), with corresponding increases for children with asthma in FVC (P < .001). FEV(1) was lower for boys with asthma than for boys without asthma (P < .001), but not for girls (P = .14). Percentages of CAMP children with abnormal FEV(1)/FVC ratios increased with age for both sexes (P < .001). The patterns of lung growth for children with asthma compared with children without asthma did not differ among children treated for 4.3 years with budesonide or nedocromil and placebo during the CAMP trial. Mild to moderate asthma results in a pattern of airway obstruction that increases in magnitude from age 5 to 18 years. Periodic spirometry is needed to monitor children with asthma for signs of increasing airway obstruction with appropriate intervention following national guidelines.

Do NHLBI lung function criteria apply to children? A cross‐sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999–2002

Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4-18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999-2002. In total, 2,728 children performed 24,388 measures. The mean +/- SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), FEV(1)/FVC ratio, and forced expiratory flow (FEF)(25-75) were 92.7 +/- 16.2, 92.2 +/- 18.0, 85.3 +/- 9.3, and 78.0 +/- 36.5 percent predicted, respectively. Seventy-seven percent of FEV(1) values were >/= 80%, 18.6% were between 60-80%, and 3.1% were <60% of predicted. FEV(1) was highest in 5-year-old children; it declined thereafter, reaching a nadir at 11 years, followed by a partial recovery from 12-18 years. Expressed in liters, FEV(1) values were lower than expected at every age, with the greatest difference at 18 years. FEV(1)/FVC ratios declined through childhood, suggesting impaired airway but not lung growth in children with asthma. In conclusion, the majority of asthmatic children attending a tertiary care facility had FEV(1) values within normal range. With increasing age, the increase in FEV(1) lags behind that of nonasthmatics, so that by 18 years, maximum FEV(1) is impaired. The NHLBI FEV(1) cutoff values do not appear to accurately stratify pediatric asthma, and no useful FEV(1) cutoff could be generated.

Sex-specific effects of asthma on pulmonary function in children.

To evaluate the effects on lung function of asthma, time since diagnosis of asthma, and age at diagnosis of asthma, we examined school children in a cohort of 2,277 fourth- and seventh-graders at least twice during a 4-yr follow-up period. Sex-specific models for each lung function were fitted through mixed-effects models that used regression splines and captured age-dependent trends in the effect of asthma on lung function. In males, a history of asthma was associated with large and statistically significant deficits in maximum midexpiratory flow (MMEF) (-4.89%) and forced expiratory flow at 75% of expired FVC (FEF(75)) (-6.62%), whereas in females these deficits were smaller (-1.93% and -2.45%, respectively) and were not statistically significant. However, larger deficits were seen in both males and females with longer time since diagnosis. In males with more than 6 yr since diagnosis, there were significant deficits in FEV(1) (-3.91%), MMEF (-7.39%), FEF(75) (-8.12%), and peak expiratory flow rate (PEFR) (-4.65%) as compared with children with less than 3 yr since diagnosis. There were fewer females with more than 6 yr since diagnosis, but deficits were similar to those of males for FEV(1) (-2.52%), MMEF (-9.26%), and FEF(75) (-14.28%). Large deficits in flow rates in both large and small airways were observed in males and females for whom asthma was reported to have been diagnosed before age 3 yr. There was little evidence that lung growth in children with asthma "catches up" at older ages. Therefore, because a constant percent deficit in lung function implies an increasingly large absolute deficit in older children with larger lungs, these results are consistent with prior evidence that lung function deficits in children with asthma persist into adulthood. We also suggest that in children, commonly observed differences between sexes in the impact of asthma on lung function may reflect differences in the duration and age of onset of asthma in males and females.

838 Impact of a prospective, randomized asthma education program on linear growth velocity and lung growth in children with asthma

838 Impact of a prospective, randomized asthma education program on linear growth velocity and lung growth in children with asthma

Volumetric Capnography and Lung Growth in Children: A Simple Model Validated

Division of Pediatric Critical Care, Saint Louis University School of Medicine, 1465 South Grand Boulevard, St. Louis, Missouri 63104–1095.In Reply: It was unfortunate that typographic errors on our part resulted in the regression coefficients published for x (Table 1) in the body weight versus phase III slope regression analysis being 10 times too large. The correct coefficients are 0.061 and 0.051 for the 8.5 and 12.5 ml *symbol* kg sup -1 tidal volumes, respectively (also 0.058 for the 8.5-ml *symbol* kg sup -1 VTin the body length regression). Using the correct coefficients, the equations are not linear.The model of normalized phase III washout slope versus age proposed by Farmery is based on the mechanism of continuous carbon dioxide evolution into a well mixed and ventilated total alveolar volume that increases with age. This mechanism is included in the pediatric single path model (SPM) along with several others not included in Farmery's model. In particular, the SPM includes the effects of gas phase convection and diffusion, airway length and diameter variations, and acinar blood flow distribution, along with blood carbon dioxide evolution and alveolar volume variation. That these other parameters are sometimes important in determining the slope of phase III of washout curves can be seen from human and animal experiments in which gas diffusivity and acinar blood flow distribution ) were varied while other parameters were held constant.In the case of carbon dioxide washout curves recorded from patients with severe COPD, the sum FRC + VT/2 either is increased or remains normal, and the normalized slope is greatly increased in comparison to normal. Equation 5 of Farmery's model would predict either no change in the normalized slopes for this case (COPD) or a decrease, whereas the SPM, with reduced acinar cross-sectional area to simulate the anatomic changes of COPD, predicts increases in phase III slope in agreement with the experimental data. .All the parameters included in the SPM may not be equally important in any given application, however the model allows simulations of the effect of airway and/or vascular pathology that are not possible in a single-compartment alveolar model. The SPM is the simplest possible theoretical model that combines the physiology of airway gas exchange, a reasonable model of airway anatomy, and the physics of gas convection, diffusion, and continued evolution from pulmonary blood.In summary, the model of Farmery is not an alternative explanation of the pediatric normalized slope versus age data but rather an insightful demonstration of what probably is, for the developing healthy human lung, the most relevant mechanism of several contained within the SPM.Robert S. Ream, M.D., Mark S. Schreiner, M.D., Joseph D. Neff, M.S.E., Karen M. McRae, M.D., Abbas F. Jawad, Ph.D., Peter W. Scherer, M.D., Ph.D., Gordon R. Neufeld, M.D., Division of Pediatric Critical Care, Saint Louis University School of Medicine, 1465 South Grand Boulevard, St. Louis, Missouri 63104–1095.

Passive smoking affects lung growth in children

Passive smoking affects lung growth in children

Environmental Tobacco Smoke: Exposure‐Response Relationships in Epidemiologic Studies

Demonstration of a dose-response relationship for environmental tobacco smoke (ETS) is an important indication of causality. Central to the analysis and interpretation of dose-response relations as described in epidemiological studies is the relationship between dose and exposure. It must be recognized that in studies of ETS we have only surrogate measures of dose, and these surrogate measures (based on exposure) are imperfect. The question-based measures of ETS exposure generally have not been standardized, may have limited validity and reliability, and cannot comprehensively describe total ETS exposure, exposure to individual ETS components, nor doses of biologically relevant agents at target sites. Nevertheless, useful data have been yielded in epidemiologic studies linking ETS exposure to increased respiratory infection and symptoms, reduced lung growth in children, and increased lung cancer in nonsmoking adults. The more consistent exposure-response data for studies on acute health in children may reflect the greater difficulty in measuring exposure in studies of chronic health in adults.

Fetal lung hypoplasia associated with maternal smoking: a morphometric analysis.

Our recently reported animal (rat) model of maternal cigarette smoke exposure during pregnancy is characterized by fetal growth retardation and lung hypoplasia. We have further defined the fetal lungs using quantitative histologic techniques. Compared to controls, lung volume at term is reduced in the experimental animals (0.28 versus 0.33 ml, p less than 0.005). Saccules (fetal "alveoli") are reduced in number (3 X 10(6) versus 5.5 X 10(6), p less than 0.005) and increased in size (average saccular volume: 35 X 10(-9) versus 21 X 10(-9) ml, p less than 0.025). These changes in size and number are consequences of reduced formation of saccule partitions (septal crests) in the experimental lungs (volume density: 0.013 versus 0.018, p less than 0.025). Internal surface area is decreased in the hypoplastic lungs (161 versus 198 cm2, p less than 0.001). The total length of parenchymal elastic tissue is diminished (224 versus 354 M, p less than 0.05). In short the hypoplastic lungs contain fewer, larger saccules and the surface potentially available for gas exchange is reduced. These results show that maternal smoking in rats adversely modifies fetal lung growth. If these observations are applicable to humans, then reduced lung growth in children of smoking mothers may begin antenatally.