RESEARCH
Research is the cornerstone of making new discoveries that could positively impact those who suffer from chronic obstructive pulmonary disease (COPD). The Polverino translational research laboratory is dedicated to understanding the pathobiology underlying COPD, and in particular the adaptive immune processes associated with pulmonary emphysema. Also, our laboratory is focused on understanding the effects of pre/peri-natals factors on the development of early airflow limitation (early COPD). Last, we are now embarking into a new research experience by exploring the effects of cigarette smoke on SARS-CoV2 infection. Polverino investigators are continually conducting research, discovering new advancements, and leading state-of-the-art studies.
LAB TECHNIQUES
Imaging: Immunohistochemistry, immunofluorescence, image mass cytometry, nanostring digital spatial profiling, electron, and confocal microscopy, laser capture microdissection, murine lung morphologic assessments of small airway remodeling, airspace enlargement, and mucous metaplasia, murine renal and peripheral muscle pathology assessment.
Cellular and molecular biology: Flow cytometry, human blood processing and immune cell isolation, human and murine organ digestion, cell culture, DNA and RNA extraction, rt-PCR, western-blot, standard ELISA, multiplex ELISA, ELISPOT, isolation of immunoglobulins from plasma, telomere length assay, snRNAseq.
Animal models: murine survival and non-survival surgery, murine pulmonary function testings (Flexivent), modeling of cigarette smoke-induced lung damage, unilateral ureter obstruction (UUO), bronchoalveolar lavage
RESEARCH STUDIES
Novel insights into adaptive immunity in COPD
Chronic obstructive pulmonary disease (COPD) is associated with abnormal pulmonary inflammation induced by noxious particles and gases most commonly present in cigarette smoke. In the last few years, activation of adaptive immune responses has emerged as an important event contributing to COPD pathogenesis. We have discovered that B-cell Activating Factor of TNF Family (BAFF), and A Proliferation-inducing Ligand (APRIL), which are key regulators of B-cell homeostasis and proliferation, and the levels of which are increased in several autoimmune diseases, are overexpressed in the peripheral lung of COPD patients. Also, we have discovered that, via BAFF production, B cells trigger a self-perpetuating mechanism of expansion of the B cell pool which is associated with the growth, in number and size, of antibody producing pulmonary lymphoid follicles. Thus, BAFF links COPD to autoimmunity, which opens up new avenues for mechanistic studies and possible therapies for the management of COPD patients. We are now investigating how the adaptive immune system contributes to the development of emphysema in COPD.
Related Publications
Polverino F, Cosio BG, Pons J, Laucho-Contreras M, Tejera P, Iglesias A, Rios A, Jahn A, Sauleda J, Divo M, Pinto-Plata V, Sholl L, Rosas IO, Agustí A, Celli BR, Owen CA. B Cell-Activating Factor. An Orchestrator of Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med. 2015 Sep 15;192(6):695-705. PMCID: PMC4595676
Polverino F, Baraldo S, Bazzan E, Agostini S, Turato G, LunardiF,Balestro E, Damin M, Papi A, Maestrelli P, CalabreseF, Saetta M. A novel insight into adaptive immunity in COPD: B cell activating factor belonging to the TNF family (BAFF). Am J Respir Crit Care Med. 2010 Oct 15;182(8):1011-9. PMID: 2058117
Polverino F, Laucho-Contreras M, Rojas Quintero J, Divo M, Pinto-Plata V, Sholl L, de-Torres JP, Celli BR, and Owen CA.Increased expression of a proliferation-inducing ligand(APRIL) in lung leukocytes and alveolar epithelial cells in COPD patients with non-small cell lung cancer: A possible link between COPD and lung cancer?Multidiscip Respir Med 2016 Apr 4; 1:17. PMCID: PMC4819280
Polverino F, Seys LJ, Bracke KR, Owen CA. B cells in chronic obstructive pulmonary disease: moving to center stage. Am J Physiol Lung Cell Mol Physiol. 2016 Oct 1;311(4):L687-L695. PMCID: PMC5142126
Sullivan JL, Bagevalu B, Glass C, Sholl LM, Kraft M, Martinez FD, Bastarrika G, de-Torres JP, Estepar RSJ, Guerra S, Polverino F†. B cell adaptive immune profile in emphysema-predominant COPD. Am J Respir Crit Care Med. 2019. Jul 26.
New insight into molecules that regulate COPD
We have published several studies in top-tier journal on the pathogenesis of COPD. First, we have shown for the first time that COPD patients and cigarette smoke (CS)-exposed mice have endothelial injury (EI) associated with increases in tissue oxidative stress- advanced glycation end products (AGEs)- receptor for AGEs (RAGE)-EI pathway in lungs and kidneys. Second, we have discovered the first protective proteinase in COPD: ADisintegrin and A Metalloproteinase Domain-8 (ADAM8), which protects the lung from CS-induced emphysema and mucus metaplasia. Third, we have shown that healthy smokers and COPD patients havereduced airway CC16 and that airway CC16 expression in COPD patients is indirectly related to COPD severity. Fourth,we have shown that Ireb2 promotes from COPD by increasing mitochondrial iron loading, and mitochondrial iron chelation alleviates cigarette smoke-induced lung damage in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.
Related Publications
Polverino F*, Rojas-Quintero J*, Wang X, Petersen H, Zhang L, Gai X, Hingham A, Zhang D, Rout A, Gupta K, Yambayev I, Pinto-Plata V, Sholl LM, Cunoosamy D, Celli BR, Goldring J, Singh D, Tesfaigzi Y, Wedzicha W, Olsoon H, Owen CA. A Disintegrin and A Metalloproteinase Domain-8 (ADAM8): A Novel Protective Proteinase in COPD. Am J Respir Crit Care Med 2018 Nov 15;198(10):1254-1267. PMCID: PMC6290938
Polverino F*, Laucho-Contreras M*, Petersen H, Bijol V, Sholl LM, Choi M, Divo M, Pinto-Plata V, Tesfaigzi Y, Celli B, Owen CA. A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in COPD. Am J Respir Crit Care Med. 2017. Jun 1;195(11):1464-1476. PMCID: PMC5470750
Laucho-Contreras M*, Polverino F*, Gupta K, Taylor K, Kelly E, Pinto-Plata V, Divo M, Ashfaq N, Petersen H, Stripp B, Pilon AL, Tesfaigzi Y, Celli B, Owen CA. Protective role for club cell secretory protein-16 (CC16) in the development of COPD. Eur Respir J. 2015 Jun;45(6):1544-56. PMCID: PMC4451404
Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M, Pabón MA, Konrad C, Polverino F, Siempos II, Perez E, Mizumura K, Ghosh MC, Parameswaran H, Williams NC, Rooney KT, Chen ZH, Goldklang MP, Yuan GC, Moore SC, Demeo DL, Rouault TA, D'Armiento JM, Schon EA, Manfredi G, Quackenbush J, Mahmood A, Silverman EK, Owen CA, Choi AM. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med. 2016 Feb;22(2):163-74. PMCID: PMC4742374
First model of cigarette smoke-induced airway disease in non-human primates
We investigated the utility of cigarette smoke (CS)-exposed cynomolgus macaque non-human primates (NHPs) as a larger animal model of COPD. NHPs exposed to CS for 12 weeks develop robust airway pathologies including small airway remodeling, mucus metaplasia, and increases in the size and number of submucosal glands. While NHPs exposed to CS for 12 weeks do not develop emphysema, they do develop pathologies that contribute to this process (pulmonary inflammation, alveolar septal cell apoptosis, increases in lung oxidative stress levels, and increased in pulmonary lymphoid follicles). Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD.
Related Publications
Polverino F, Doyle-Eisele M, McDonald J, Kelly EM, Wilder J, Royer C, Laucho-Contreras M, Mauderly J, Divo M, Pinto-Plata V, Celli BR, Tesfaigzi Y, Owen CA. A Novel Non-Human Primate Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. Am. J. Pathol. 2015 Mar;185(3):741-55. PMCID: PMC4348468
Polverino F, Doyle-Eisele M, McDonald J, Kelly EM, Wilder J, Mauderly J, Divo M, Pinto-Plata V, Celli BR, Tesfaigzi Y, Owen CA. A Novel Non-Human Primate Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. Eur Respir J 2014; 44: Suppl. 58, 864 (Abstract).
Polverino F, Doyle-Eisele M, McDonald J, Kelly EM, Wilder J, Royer C, Laucho-Contreras M, Mauderly J, Divo M, Pinto-Plata V, Celli BR, Tesfaigzi Y, Owen CA. A Novel Non-Human Primate Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. Am. J. Pathol. 2015 Mar;185(3):741-55. PMCID: PMC4348468
New clinical insight into COPD
We have published several clinical studies focused on COPD pathophysiology and clinical observations. We have analyzed the factors determining the early onset of COPD in the Lovelace Smokers Cohort, and found that low lung function and rapid decline of lung function of 40 ml/year might help detect those smokers at the highest risk of incident COPD. With the BODE Collaborative group, we have assessed the differences between 2015 and 2017 GOLD guidelines. Compared with 2015, the GOLD ABCD 2017 classification significantly shifts patients from grades C and D to categories A and B. The GOLD 2017 equalize the Charlson comorbidity score in all groups and minimizes the differences in BODE between groups B and D, making the risk of death similar between them. We have also shown that dietary supplementation with CoQ10 and Creatine improves functional performance, body composition and perception of dyspnea in patients with COPD.
Related Publications
Petersen H, Sood A, Polverino F, Owen CA, Pinto-Plata V, Celli BR, Tesfaigzi Y.The Course of Lung Function in Middle-aged Heavy Smokers: Incidence and Time to Early Onset of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2018 Dec 1;198(11):1449-1451. PMCID: PMC6290951
Cabrera López C, Casanova Macario C, Marín Trigo JM, de-Torres JP, Sicilia Torres R, González JM, Polverino F, Divo M, Pinto Plata V, Zulueta JJ, Celli B. Comparison of the 2017 and 2015 Global Initiative for Chronic Obstructive Lung Disease Reports. Impact on Grouping and Outcomes. Am J Respir Crit Care Med. 2018 Feb 15;197(4):463-469. PMID: 29099607
De Benedetto F, Pastorelli R, Ferrario M, de Blasio F, Marinari S, Brunelli L, Wouters EFM, Polverino F, Celli BR. Supplementation with Qter® and Creatine improves functional performance in COPD patients on long term oxygen therapy. Respir Med. 2018 Sep;142:86-93. PMID: 30170808
Polverino M, Capuozzo A, Cicchitto G, Ferrigno F, Mauro I, Santoriello C, Sirignano E, Aliverti A, Celli B, Polverino F†. Smoking Pattern in Men and Women: A Possible Contributor to Gender Differences in Smoke-related Lung Diseases. Am J Respir Crit Care Med. 2020 Jun 1.
Polverino F, Celli B. The Challenge of Controlling the COPD Epidemic: Unmet Needs. Am J Med. 2018 Sep;131(9S):1-6. PMID: 29778456
Polverino F, Sam A, Guerra S. COPD: to be or not to be. That is the question. Am. J Med. 2019 Nov;132(11):1271-1278.
Early Origins of Airflow Limitation (Early COPD)
Many knowledge gaps in the nature of early Chronic Obstructive Pulmonary Disease (COPD) still exist, mainly because COPD has always been considered a disease of the elderly. Little attention has been paid to the pathologic changes in the lungs of young adults with risk factors for COPD, such as bronchopulmonary dysplasia. One major limitation is the current lack of non-invasive ways to sensitively measure and/or image functional declines from subjects who are at risk for COPD but haven’t yet developed more significant clinical symptoms of the disease. We have tested the use of lung magnetic resonance (MRI) with hyperpolarized gas in the identification of lung abnormalities in patients with bronchopulmonary dysplasia with underlying chronic airflow limitation, who meet the spirometry criteria for early-onset COPD. In the post-surfactant era, where more young-adults will be spirometrically diagnosed with COPD, patients should be classified not only on the basis of their airflow limitation, but also on lung abnormalities identified with safe, comprehensive imaging technologies which allow regular, longitudinal follow up.
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Polverino F. et al. AM J Med. 2020
Related Publications
Polverino F †, Hysinger EB, Gupta N, Willmering M, Olin T, Abman SH, Woods JC. Lung MRI as a potential complementary differential diagnostic tool for early COPD. Am J Med. 2020 Jun;133(6):757-760.
Polverino F†, Soriano J. Small Airways and Early Origins of COPD: Pathobiological and epidemiological considerations. Eur. Resp. J. 2020. In press.
RESEARCH SUPPORT
Ongoing Research Support
R01 HL149744 (PI: F. Polverino) 5.4 calendar months 09/2020-09/2025
NIH/NHLBI
Title: B cell adaptive immune profile in emphysema-predominant COPD
The goal of this proposal is to determine the mechanism by which B cells induce lung tissue damage in a subset of COPD patients with computed tomography-defined emphysema.
Role: PI
R01 HL149744 (PI: F.D. Martinez) 0.9 calendar months 04/2020-03/2025
NIH/NHLBI
Title: Early Origins of Chronic Lung Disease: Outcomes into the Fifth Decade of Life
The goal of this proposal is to determine the mechanism by which subjects develop chronic airflow limitation starting from the first years of their life
Role: Co-PI
Completed Research Support
Flight Attendants Medical Research Institute
Parker B. Francis
American Lung Association
Department of Defense
European Respiratory Society