Airflow Obstruction In Smokers Research Articles

The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects

Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.

Childhood-Onset Asthma in Smokers. Association between CT Measures of Airway Size, Lung Function, and Chronic Airflow Obstruction

Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

COPD prognosis in relation to diagnostic criteria for airflow obstruction in smokers

The aim of this study was to establish which cut-off point for the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (i.e. fixed 0.70 or lower limit of normal (LLN) cut-off point) best predicts accelerated lung function decline and exacerbations in middle-aged smokers. We performed secondary analyses on the Lung Health Study dataset. 4045 smokers aged 35-60 years with mild-to-moderate obstructive pulmonary disease were subdivided into categories based on presence or absence of obstruction according to both FEV1/FVC cut-off points. Post-bronchodilator FEV1 decline served as the primary outcome to compare subjects between the categories. 583 (14.4%) subjects were nonobstructed and 3230 (79.8%) subjects were obstructed according to both FEV1/FVC cut-off points. 173 (4.3%) subjects were obstructed according to the fixed cut-off point, but not according to the LLN cut-off point ("discordant" subjects). Mean±SE post-bronchodilator FEV1 decline was 41.8±2.0 mL·year(-1) in nonobstructed subjects, 43.8±3.8 mL·year(-1) in discordant subjects and 53.5±0.9 mL·year(-1) in obstructed subjects (p<0.001). Our study showed that FEV1 decline in subjects deemed obstructed according to a fixed criterion (FEV1/FVC <0.70), but non-obstructed by a sex- and age-specific criterion (LLN) closely resembles FEV1 decline in subjects designated as non-obstructed by both criteria. Sex and age should be taken into account when assessing airflow obstruction in middle-aged smokers.

Chronic bronchitis and chronic obstructive pulmonary disease.

Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.

The Role of Bactericidal/Permeability-Increasing Protein in Men with Chronic Obstructive Pulmonary Disease

Background and objective: Bactericidal/permeability-increasing protein (BPI) is a member of the pattern recognition receptors of the innate immune system. Recently, an association between genetic polymorphism in the BPI gene and a risk of airflow decline after transplantation was demonstrated, but whether these findings are reproducible in nontransplantation populations, such as those with COPD, is still unknown. The aim of this study is to explore the role of BPI in COPD. Methods: The genotypes of 107 patients with COPD and 110 control subjects were evaluated by polymerase chain reaction and polymorphism analysis of the BPI genes and ELISA analysis of the plasma BPI level. All subjects were men over 40 years old who smoked. Results: BPI mutation PstI (T→C) polymorphism in intron 5 was associated with an increased risk of developing COPD (OR 3.73, 95%CI: 1.62–9.10), and the frequency was significantly increased in the COPD group compared with the control group (26/107 [24.3%] vs 12/110 [10.9%], p = 0.002). In addition, COPD patients exhibited a decreased plasma level of BPI compared with the control group (10.6 ± 2.2 vs 23.4 ± 2.1ng/ml, p < 0.0001). Conclusions: BPI mutation (PstI in intron 5) and a decreased plasma BPI level were significant risk factors in susceptibility to COPD. These results demonstrate that BPI genetic mutation and impaired BPI production or release may result in airflow obstruction in smokers.

Prevalence of airflow obstruction in smokers and never-smokers in Switzerland

The aim of the present study was to measure age-specific prevalence of airflow obstruction in Switzerland in smokers and never-smokers using pulmonary function tests and respiratory symptoms from 6,126 subjects participating in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults. The lower limit of normal of the forced expiratory volume in 1 s/forced vital capacity ratio was used to define airflow obstruction. Severity of airflow obstruction was graded according to the recommendations of the Global Initiative for Chronic Obstructive Lung Disease. Prevalence of airflow obstruction ranged from 2.5% in subjects aged 30-39 yrs to 8.0% in those aged ≥ 70 yrs. In multivariate analysis, age (OR 2.8, ≥ 70 yrs versus 30-39 yrs), smoking (OR 1.8) and asthma (OR 6.7) were associated with airflow obstruction. Never-smokers constituted 29.3% of subjects with airflow obstruction. Never-smokers with airflow obstruction were younger, more likely to be male and reported asthma more frequently than obstructive smokers. Obstructive smokers and never-smokers had similar level of symptoms and quality of life impairment. The prevalence of airflow obstruction in Switzerland is similar to other developed countries. Never-smokers account for a third of the prevalence, which is higher proportion than elsewhere. Airflow obstruction in never-smokers deserves attention because of its frequency and its similar health impact to that in smokers.

Variability of the Prevalence of Undiagnosed Airflow Obstruction in Smokers Using Different Diagnostic Criteria

To estimate the prevalence of undiagnosed airflow obstruction (AFO) in Hong Kong smokers with no previous diagnosis of respiratory disease, and to assess its variability when applying different prediction equations and diagnostic criteria. A multicenter, population-based, cross-sectional prevalence study was performed in smokers aged 20 to 80 years. Three different criteria (fixed 70% [Global Initiative for Chronic Obstructive Lung Disease and British Thoracic Society], fixed 75%, and European Respiratory Society [ERS]) were applied to define a lower limit of normal (LLN) of the FEV(1)/FVC ratio to compare with the Hong Kong Chinese reference equation (criterion 1), which had used a distribution-free method to obtain the lower fifth percentile of FEV(1)/FVC ratio as the LLN. In 525 male patients, using criterion 1 (local internal prediction equation) and defining AFO as FEV(1)/FVC less than LLN, the overall prevalence of AFO was 13.7%: 8.3% in age > or = 20 to 40 years, 14.0% in age > or = 40 to 60 years, and 17.8% in age > or = 60 to 80 years. When the local internal prediction equation was used as the comparison reference, the fixed-ratio methods tended to miss AFO in younger age groups and overdiagnose AFO in old age, while the ERS criteria, which uses an almost lower fifth percentile-equivalent method, showed less of such a trend but still only showed moderate agreement with criterion 1. Undiagnosed AFO was prevalent in Hong Kong smokers. Estimated prevalence rates were highly affected by the criteria used to define AFO. The predicted lower fifth percentile values calculated from a local reference equation as the LLN of FEV(1)/FVC ratio should be used for the diagnosis of AFO.

Epithelial Mucin Stores Are Increased in the Large Airways of Smokers With Airflow Obstruction

Habitual cigarette smoking is associated with chronic mucus hypersecretion, but the relationship between mucus abnormalities and airflow obstruction in smokers is uncertain. We collected bronchial biopsy samples and epithelial brushings from 24 smokers with and without airflow obstruction and 19 nonsmoking healthy control subjects. Epithelial mucin stores, mucin immunostains, and goblet cell morphology were quantified in bronchial biopsy samples using stereology, and mucin gene expression was quantified in epithelial brushings using real-time reverse transcriptase-polymerase chain reaction. Goblet cell size and number were higher than normal in smokers (both p < 0.05), leading to a 2.2-fold increase in the volume of stored mucin in the epithelium per surface area of basal lamina (1.94 +/- 0.31 microm(3)/microm(2) vs 4.32 +/- 0.55 microm(3)/microm(2) in control subjects vs smokers, p = 0.001). The increase in stored mucin occurred because of an increase in MUC5AC (p = 0.018) and despite a decrease in MUC5B (p < 0.0001). Stored mucin was significantly higher in the subgroup of smokers with airflow obstruction (p = 0.029) and correlated with FEV(1)/FVC even when controlling for diffusing capacity as a measure of emphysema (p = 0.034). Epithelial mucin stores are increased in habitual smokers because of goblet cell hypertrophy and hyperplasia, and the pattern of mucin gene expression is abnormal. The highest epithelial mucin stores are found in smokers with airflow obstruction, suggesting a mechanistic link between epithelial mucin dysregulation and airflow obstruction.

Hepatocyte and keratinocyte growth factors and their receptors in human lung emphysema

BackgroundHepatocyte and keratinocyte growth factors are key growth factors in the process of alveolar repair. We hypothesized that excessive alveolar destruction observed in lung emphysema involves impaired expression of hepatocyte and keratinocyte growth factors or their respective receptors, c-met and keratinocyte growth factor receptor. The aim of our study was to compare the expression of hepatocyte and keratinocyte growth factors and their receptors in lung samples from 3 groups of patients: emphysema; smokers without emphysema and non-smokers without emphysema.MethodsHepatocyte and keratinocyte growth factor proteins were analysed by immunoassay and western blot; mRNA expression was measured by real time quantitative polymerase chain reaction.ResultsHepatocyte and keratinocyte growth factors, c-met and keratinocyte growth factor receptor mRNA levels were similar in emphysema and non-emphysema patients. Hepatocyte growth factor mRNA correlated negatively with FEV1 and the FEV1/FVC ratio both in emphysema patients and in smokers with or without emphysema. Hepatocyte and keratinocyte growth factor protein concentrations were similar in all patients' groups.ConclusionThe expression of hepatocyte and keratinocyte growth factors and their receptors is preserved in patients with lung emphysema as compared to patients without emphysema. Hepatocyte growth factor mRNA correlates with the severity of airflow obstruction in smokers.

Prevalence of undetected persistent airflow obstruction in male smokers 40–65 years old

Airflow obstruction in smokers is often diagnosed relatively late. Earlier detection of airflow obstruction and smoking cessation may result in significant health gain. To determine the prevalence of previously undetected persistent airflow obstruction according to WHO/GOLD criteria in male smokers aged 40 to 65 years and its correlation with age, smoking history and the presence of coughing. In a cross-sectional study among 805 male smokers aged 40-65 years spirometry was performed according to ATS recommendations. In participants with low lung function (FEV1 < 85% predicted) a bronchodilator test was performed. In 702 participants [mean age 50 years (SD 6.6), mean number of pack years 24.7 (SD 9.6)] with acceptable spirometric curves, previously undetected airflow obstruction was found in 210 subjects (29.9%; 95% CI 26.5-33.4): mild airflow obstruction (GOLD stage 1) in 182 subjects (25.9%; 22.7-29.3) and moderate airflow obstruction (GOLD stage 2) in 28 (4.0%; 2.7-5.7). In the older age group (>55 years) airflow obstruction (GOLD 1 or higher) was found in 45% versus 21% in the youngest age group (40-44 years). In subjects with > or =30 pack years the prevalence of airflow obstruction was 45% versus 20% among those with <20 pack years. In smokers reporting coughing the prevalence was 47% versus 25% in those not reporting this symptom. The prevalence of undetected persistent airflow obstruction in middle-aged smokers is high. Targeted screening therefore, especially in smokers aged 40-65 years needs to be considered.

Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization.

Factors modulating the variable progression of chronic obstructive pulmonary disease (COPD) are largely unknown, but infectious agents may play a role. Because Pneumocystis has previously been shown to induce a CD8(+) lymphocyte- and neutrophil-predominant response similar to that in COPD, we explored the association of the organism with accelerated disease progression. We examined Pneumocystis colonization rates in lung tissue obtained during lung resection or transplantation in smokers with a range of airway obstruction severity and in a control group with lung diseases other than COPD. Using nested polymerase chain reaction, Pneumocystis colonization was detected in 36.7% of patients with very severe COPD (Global Health Initiative on Obstructive Lung Disease [GOLD] Stage IV) compared with 5.3% of smokers with normal lung function or less severe COPD (Stages 0, I, II, and III) (p = 0.004) and with 9.1% of control subjects (p = 0.007). Colonized subjects exhibited more severe airway obstruction (median FEV(1) = 21% predicted versus 62% in noncolonized subjects, p = 0.006). GOLD IV was the strongest predictor of Pneumocystis colonization (odds ratio = 7.3, 95% confidence interval = 2.4-22.4, p < 0.001) and was independent of smoking history. We conclude that there is a strong association between Pneumocystis colonization and severity of airflow obstruction in smokers, suggesting a possible pathogenic link with COPD progression.

Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes.

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.

Role of Endogenous Nitric Oxide in Airflow Obstruction in Smokers

The aim of this study was to examine the relationship between endogenous nitric oxide (NO) level and airflow obstruction in smokers using single-breath measurement of exhaled NO with the sequential breath-holding method. A university hospital. Nine nonsmoking and ten smoking healthy volunteers. NO in exhaled air was measured using a chemiluminescence analyzer. Pulmonary function tests were performed using an autospirometer. The level of exhaled NO was higher in nonsmokers than in smokers, and the difference became larger as the breath-holding time increased. To evaluate the correlation between endogenous NO level and the degree of airflow obstruction in smokers, we used a new parameter, the NO concentration difference (delta NO). Our findings indicate that reduced level of NO in exhaled air is an indicator of decreased NO synthesis within the respiratory system and is associated with the development of airflow obstruction in smokers (r = 0.678; p < 0.01). delta NO is a good indicator of the synthesis of endogenous NO within the respiratory system, and it appears likely that the reduced synthesis of NO may be a contributing factor to airflow obstruction in smokers.

The relationship between facial wrinkling and airflow obstruction.

Similar smoking-related changes in the collagen and elastin could play a role in the pathogenesis of both skin wrinkling and chronic airflow obstruction. The hypothesis was tested by analyzing whether increased facial wrinkling, especially in smokers, is associated with the presence of airflow obstruction. An age-stratified randomized sample of the general population comprising 6034 men and 7152 women between 30 and 80 years of age was analyzed. The recording of wrinkling in the crow's foot area of the right eye was performed according to an earlier described severity score. As an index of airflow obstruction, we used the ratio between forced expiratory volume in 1 s and forced vital capacity in percent (FEV1/FVC%). Multiple regression analysis comprising current and previous smokers showed that, after controlling for age, subjects with highest wrinkle scores had on average FEV1/FVC% that was 1.2-1.9% lower than in subjects with lower wrinkle scores. No association between facial wrinkling and airflow obstruction was observed among lifetime nonsmokers. Increased facial wrinkling is independent of age when associated with airflow obstruction in smokers, but not in never-smokers. The magnitude of this association, however, is small.

A prospective evaluation of plain radiographic signs of chronic obstructive pulmonary disease

Plain film signs of COPD, spirometric evidence of airflow obstruction, and smoking history were correlated in a group of 182 men aged 32 to 85 years (average, 57.5 years) who presented for evaluation of possible pulmonary disability. There were 148 current or past smokers (range, 0.66 to 150 pack-years; average, 31.89 pack-years) and 34 lifetime nonsmokers. A single observer, who had no knowledge of the other parameters, prospectively evaluated posteroanterior chest radiographs for 11 signs of COPD. Airflow obstruction was defined as a reduction in FEV1/FVC% below the 95% confidence limit of normal. Obstruction was classified on the basis of the reduction in FEV1 as mild (FEV1 greater than 2.5L), moderate (FEV1 greater than 1.0 L and less than 2.5 L), or severe (FEV1 less than 1.0 L). Spirometric evidence of airflow obstruction was present in 67 patients; obstruction was mild in 26, moderate in 36, and severe in 5. We found a statistically significant association between smoking and airflow obstruction on spirometry (P less than 0.001) and an equally significant association between smoking and radiographic signs of COPD on plain chest films (P less than 0.001). Both airflow obstruction and radiologic signs of COPD were generally absent in lifetime nonsmokers. The plain film signs of COPD were only of moderate value in predicting spirometric evidence of airflow obstruction in smokers; spirometric evidence is not the gold standard for the presence of COPD, however, and the strong association between smoking and these radiologic signs may indicate that in smokers the presence of plain film signs of COPD reflects morphologic abnormality in the lungs indicative of disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Observations on the pathogenesis of chronic airflow obstruction in smokers: implications for the detection of "early" lung disease.

Observations on the pathogenesis of chronic airflow obstruction in smokers: implications for the detection of "early" lung disease.

Postmortem evaluation of airflow limitation in obstructive lung disease.

ArticlePostmortem evaluation of airflow limitation in obstructive lung disease.S S Park, O H Yoo, M Janis, and M H Williams JrS S Park, O H Yoo, M Janis, and M H Williams JrPublished Online:01 Sep 1969https://doi.org/10.1152/jappl.1969.27.3.308MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByLung Mechanics in Disease1 January 2011Observations on the pathogenesis of chronic airflow obstruction in smokers: implications for the detection of "early" lung disease.Thorax, Vol. 41, No. 2Chronic airflow obstruction: Evolution of disordered function in cigarette smokers1 May 1985 | Medical Journal of Australia, Vol. 142, No. 11Störungen des LuftgehaltesMethods and Results of Postmortem Studies of Airway Dynamics in Normal Lungs and Lungs with Minimal ObstructionCorrelation Between Functional and Morphometrical Parameters in Chronic Obstructive Lung DiseaseThe correlation of lung structure with functionLung, Vol. 160, No. 1INTRATHORACIC AIRWAY MECHANICS IN PATIENTS WITH EMPHYSEMADie obstruktiven Atemwegserkrankungen: Morphologie und klinisch-pathologische KorrelationPeripheral pooling of bronchographic contrast material: evidence of its relationship to smoking and emphysema.Thorax, Vol. 33, No. 2Indices de obstruccion bronquialArchivos de Bronconeumología, Vol. 12, No. 4Factors Determining the Shape of Maximum Expiratory Flow-Volume Curves in Childhood Asthma25 March 2008 | Australian and New Zealand Journal of Medicine, Vol. 3, No. 6Failure of Body Plethysmography to Reflect Functional Deterioration Seen in Chronic Obstructive Pulmonary DiseaseChest, Vol. 63, No. 3Central Airway Resistance in Excised Emphysematous LungsChest, Vol. 61, No. 7Clinical Experience with a New Test of Pulmonary FunctionChest, Vol. 60, No. 2Pulmonary Effects of Sulfur Dioxide Exposure in the Syrian HamsterArchives of Environmental Health: An International Journal, Vol. 21, No. 1 More from this issue > Volume 27Issue 3September 1969Pages 308-12 https://doi.org/10.1152/jappl.1969.27.3.308PubMed5804124History Published online 1 September 1969 Published in print 1 September 1969 Metrics