ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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Secondhand Smoke Alters Alveolar Macrophage Gene Expression
Session Title
TP41 - TP041 DIAGNOSIS AND RISK ASSESSMENT IN COPD
Abstract
A2318 - Secondhand Smoke Alters Alveolar Macrophage Gene Expression
Author Block: S. O'Beirne1, J. Salit1, N. E. Alexis2, M. Arjomandi3, I. Barjaktarevic4, P. Basta5, R. P. Bowler6, S. A. Christenson7, S. M. Cloonan8, J. L. Curtis9, C. M. Doerschuk10, M. B. Drummond11, A. T. Hastie12, Y. J. Huang13, V. Kim14, W. K. O'Neal15, V. E. Ortega16, L. Postow17, N. Putcha18, S. I. Rennard19, J. M. Wells20, P. Woodruff21, W. Z. Zhang22, R. G. Crystal1, R. J. Kaner1, SPIROMICS Investigators; 1Weill Cornell Medical College, New York, NY, United States, 2Univ of North Carolina, Chapel Hill, NC, United States, 3San Francisco VA Medical Center, Univ of California San Francisco, San Francisco, CA, United States, 4Pulmonary and Critical Care, UCLA, Los Angeles, CA, United States, 5The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 6Natl Jewish Health, Denver, CO, United States, 7Pulmonary & Critical Care, University of California- San Francisco, San Francisco, CA, United States, 8Pulmonary, Weill Cornell Medical College, New York City, NY, United States, 9Internal Medicine, Univ of Michigan Hlth System, Ann Arbor, MI, United States, 10Univ of N Carolina, Chapel Hill, NC, United States, 11Medicine-Pulmonary, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 12Dept Int Med - Pulmonary, Wake Forest Univ BAptist Med Ctr, Winston Salem, NC, United States, 13Pulmonary/Critical Care, Univ of Michigan, Ann Arbor, MI, United States, 14Thoracic Medicine and Surgery, Temple Lung Center, Philadelphia, PA, United States, 15Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 16Wake Forest School of Medicine, Winston Salem, NC, United States, 17NIH, Bethesda, MD, United States, 18Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States, 19Internal Medicine, UNMC, Omha, NE, United States, 20Pulmonary, Allergy, and Critical Care Medicine, UAB, Birmingham, AL, United States, 21Medicine, University of California, San Francisco, San Francisco, CA, United States, 22Internal Medicine - Division of Pulmonary and Crtical Care, New York Presbyterian - Weill Cornell Medicine, New York, NY, United States.
Rationale: Secondhand smoke is known to have numerous adverse health effects. Alveolar macrophages (AM) are central to orchestrating the lung host immune response and play an important role in the development of chronic obstructive pulmonary disease (COPD) and emphysema. We hypothesized that secondhand smoke exposure would correlate with AM gene expression patterns affecting key biologic functions.
Methods: We used RNA-sequencing to quantify gene expression of AM, purified by adherence, in participants (N=156) evaluated in the bronchoscopy substudy of the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS; ClinicalTrials.gov NCT01969344T4), an observational cohort of never, former and current smokers including individuals with COPD. We used Pearson dissimilarity hierarchical clustering to analyze gene expression, which we then compared to 95 clinical, physiologic, and radiographic covariates. Nonsmoking participants with secondhand smoke exposure (never-smokers N=23; ex-smokers N=32; and COPD ex-smokers N=33) were queried about hours of exposure in the previous 7 days.
Results: Unsupervised hierarchical clustering of 17,913 expressed genes for the entire cohort (N=156) yielded three major transcription-associated clusters. Secondhand smoke exposure was the covariate most highly correlated with the 3 expression clusters (Kruskal-Wallis p<5x10-9). Among the nonsmoking participants (N=88), significant Spearman correlations between hours of secondhand smoke exposure and gene expression were observed in 73 AM genes (with Benjamini-Hochberg correction p(BH) <0.05). The most highly correlated gene CDK5RAP2 (r=0.50, p(BH)=0.013), a pericentriolar protein that functions in centrosomal attachment, is known to be induced in vitro by exposure of human monocyte-derived macrophages to benzo(a)pyrene, a component of secondhand smoke. If individuals with COPD were removed from the analysis (N=55 remaining), then expression of 435 genes (including 56 of the original 73 genes) correlated with secondhand smoke exposure. When we further analyzed these genes using the PantherDB Overrepresentation Test, regulation of kinase activity, phosphatidylinositol and DNA-related biological processes and molecular functions were significantly associated with second-hand smoke exposure. OTULIN was the gene with the strongest correlation (r=0.624, p(BH) = 0.0063) of expression to secondhand smoke exposure. OTULIN is a deubiquitinase involved in control of the inflammasome and downregulates the NF-kB response to TNF-α.
Conclusions: These data provide new evidence that secondhand smoke exposure alters the pattern of AM gene expression affecting immune-inflammatory processes involved in the pathogenesis of COPD and emphysema.
Author Block: S. O'Beirne1, J. Salit1, N. E. Alexis2, M. Arjomandi3, I. Barjaktarevic4, P. Basta5, R. P. Bowler6, S. A. Christenson7, S. M. Cloonan8, J. L. Curtis9, C. M. Doerschuk10, M. B. Drummond11, A. T. Hastie12, Y. J. Huang13, V. Kim14, W. K. O'Neal15, V. E. Ortega16, L. Postow17, N. Putcha18, S. I. Rennard19, J. M. Wells20, P. Woodruff21, W. Z. Zhang22, R. G. Crystal1, R. J. Kaner1, SPIROMICS Investigators; 1Weill Cornell Medical College, New York, NY, United States, 2Univ of North Carolina, Chapel Hill, NC, United States, 3San Francisco VA Medical Center, Univ of California San Francisco, San Francisco, CA, United States, 4Pulmonary and Critical Care, UCLA, Los Angeles, CA, United States, 5The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 6Natl Jewish Health, Denver, CO, United States, 7Pulmonary & Critical Care, University of California- San Francisco, San Francisco, CA, United States, 8Pulmonary, Weill Cornell Medical College, New York City, NY, United States, 9Internal Medicine, Univ of Michigan Hlth System, Ann Arbor, MI, United States, 10Univ of N Carolina, Chapel Hill, NC, United States, 11Medicine-Pulmonary, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 12Dept Int Med - Pulmonary, Wake Forest Univ BAptist Med Ctr, Winston Salem, NC, United States, 13Pulmonary/Critical Care, Univ of Michigan, Ann Arbor, MI, United States, 14Thoracic Medicine and Surgery, Temple Lung Center, Philadelphia, PA, United States, 15Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 16Wake Forest School of Medicine, Winston Salem, NC, United States, 17NIH, Bethesda, MD, United States, 18Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States, 19Internal Medicine, UNMC, Omha, NE, United States, 20Pulmonary, Allergy, and Critical Care Medicine, UAB, Birmingham, AL, United States, 21Medicine, University of California, San Francisco, San Francisco, CA, United States, 22Internal Medicine - Division of Pulmonary and Crtical Care, New York Presbyterian - Weill Cornell Medicine, New York, NY, United States.
Rationale: Secondhand smoke is known to have numerous adverse health effects. Alveolar macrophages (AM) are central to orchestrating the lung host immune response and play an important role in the development of chronic obstructive pulmonary disease (COPD) and emphysema. We hypothesized that secondhand smoke exposure would correlate with AM gene expression patterns affecting key biologic functions.
Methods: We used RNA-sequencing to quantify gene expression of AM, purified by adherence, in participants (N=156) evaluated in the bronchoscopy substudy of the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS; ClinicalTrials.gov NCT01969344T4), an observational cohort of never, former and current smokers including individuals with COPD. We used Pearson dissimilarity hierarchical clustering to analyze gene expression, which we then compared to 95 clinical, physiologic, and radiographic covariates. Nonsmoking participants with secondhand smoke exposure (never-smokers N=23; ex-smokers N=32; and COPD ex-smokers N=33) were queried about hours of exposure in the previous 7 days.
Results: Unsupervised hierarchical clustering of 17,913 expressed genes for the entire cohort (N=156) yielded three major transcription-associated clusters. Secondhand smoke exposure was the covariate most highly correlated with the 3 expression clusters (Kruskal-Wallis p<5x10-9). Among the nonsmoking participants (N=88), significant Spearman correlations between hours of secondhand smoke exposure and gene expression were observed in 73 AM genes (with Benjamini-Hochberg correction p(BH) <0.05). The most highly correlated gene CDK5RAP2 (r=0.50, p(BH)=0.013), a pericentriolar protein that functions in centrosomal attachment, is known to be induced in vitro by exposure of human monocyte-derived macrophages to benzo(a)pyrene, a component of secondhand smoke. If individuals with COPD were removed from the analysis (N=55 remaining), then expression of 435 genes (including 56 of the original 73 genes) correlated with secondhand smoke exposure. When we further analyzed these genes using the PantherDB Overrepresentation Test, regulation of kinase activity, phosphatidylinositol and DNA-related biological processes and molecular functions were significantly associated with second-hand smoke exposure. OTULIN was the gene with the strongest correlation (r=0.624, p(BH) = 0.0063) of expression to secondhand smoke exposure. OTULIN is a deubiquitinase involved in control of the inflammasome and downregulates the NF-kB response to TNF-α.
Conclusions: These data provide new evidence that secondhand smoke exposure alters the pattern of AM gene expression affecting immune-inflammatory processes involved in the pathogenesis of COPD and emphysema.
