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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, immunofluorescenceimage mass cytometry, 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, single cell RNAseq.

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, intrauterine therapeutic injections

RESEARCH STUDIES

Novel insights into adaptive immunity in COPD

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), a key regulator of B-cell homeostasis and proliferation, and the levels of which are increased in several autoimmune diseases, is 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. We have also recently shown that patients with emphysema-predominant COPD have upregulated B cell responses in their lungs vs. COPD patients with a lesser degree of emphysema, irrespectively of the degree of airflow limitation. Last, we have found similarities between the T cell immune lung compartment in patients with COPD and NSCLC, that could unveil some common mechanisms underlying the onset and progression of both diseases. Last, we have identified a T cell immune signature in patients with COPD that renders them more susceptible to SARS-CoV 2-associated lung disease. 

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.

Polverino F†, Mirra D, Esposito R, Spaziano G, Sgambato M, Piegari E, Cozzolino A, Cione E, Gallelli L, CapuozzoA, C. Santoriello, Berrino L, de-Torres J.P., Polverino M, D'Agostino B. Similar Programmed Death Ligand 1 (PD-L1) expression profile in patients with mild COPD and lung cancer. Sci. Rep. 2022. PMID: 36575294

 

Yang CX, Tomchaney M, Landecho MF, Zamacona BR, Marin Oto M, Zulueta J, Malo J, Knoper S, Contoli M, Papi A, Vasilescu DM, Sauler M, Straub C, Tan C, Martinez FD, Bhattacharya D, Rosas IO, Kheradmand F, Hackett TL, Polverino F†. Lung Spatial Profiling Reveals a T Cell Signature in COPD Patients with Fatal SARS-CoV-2 Infection. Cells. 2022 Jun 7;11(12):1864. PMID: 35740993

New insight into molecules that regulate COPD

First, we have shown for the first time that COPD patients and cigarette smoke (CS)-exposed mice have endothelial injury associated with increases in tissue oxidative stress- advanced glycation end products (AGEs)- receptor for AGEs (RAGE)-endothelial injury 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. We have also recently shown that delivery of exogenous CC16 protects the lung from CS-induced pathologies. Last, we have showed for the first time that CC16 binds to the VLA4 receptor on blood leukocytes. Our studies on CC16 have paved the way to therapies aimed at boosting CC16 levels, that have the potential to tackle the aging effects of CS in COPD, and to improve the lung function in those with lower pulmonary levels of CC16. 

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

 

Rojas-Quintero JL, Wang X, Fucci QA, Burkett PR, Kim SK, Zhang D, Tesfaigzi Y, Li Y, Bhashyam AR, Zhang L, Khamas H, Celli BR, Pilon AL, Polverino F, Owen CA. CC16 augmentation reduces exaggerated COPD-like disease in Cc16-deficient mice. JCI Insight 2023; In Press.

Preclinical models of COPD and asthma

In our laboratory, we use a well-established COPD-like murine model obtained by exposing the mice to mixed mainstream and side stream cigarette smoke. We have also 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.

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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*, 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. PMID: 28085500

Polverino F†, Wu TD, Rojas-Quintero J, Wang X, Mayo J, Tomchaney M, Tram J, Zhang D, Cleveland KH, Cordoba-Lanus E, Owen CA, Fawzy A, Kinney GL, Hersh CP, Hansel NH, Doubleday K, Tesfaigzi Y, Ledford JG, Casanoca C, Zmijewski J, Konhilas J, Langlais PR, Schnellmann R, McCormack M, Celli B. Metformin: experimental and clinical evidence for a potential role in emphysema treatment. Am J Respir Crit Care Med 2021 Sep 15;204(6):651-666. PMID: 34033525

Clinical and translational studies on COPD

We have published several clinical studies focused on COPD pathophysiology and clinical observations. We have showed for the first time that the biguanide metformin protects against emphysema progression in patients with COPD, and against smoke-induced lung pathologies in a COPD murine model. These pathologies are associated with fixed airflow limitation early in life even in absence of cigarette smoke exposure. 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. We have also found critical differences in the cigarette smoking pattern between men vs. women, that could explain some differences in prevalence of COPD and lung cancer in men vs. women. Last, we have assessed the difference in plasma metabolomic profile between patients with COPD and controls, and correlated such profile with clinical COPD outcomes

Related Publications

Polverino F†, Wu TD, Rojas-Quintero J, Wang X, Mayo J, Tomchaney M, Tram J, Zhang D, Cleveland KH, Cordoba-Lanus E, Owen CA, Fawzy A, Kinney GL, Hersh CP, Hansel NH, Doubleday K, Tesfaigzi Y, Ledford JG, Casanoca C, Zmijewski J, Konhilas J, Langlais PR, Schnellmann R, McCormack M, Celli B. Metformin: experimental and clinical evidence for a potential role in emphysema treatment. Am J Respir Crit Care Med 2021 Sep 15;204(6):651-666. PMID: 34033525

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. 

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. 

We have also assessed the influence of early-life determinant on the pathogenesis of chronic airflow limitation, and demonstrated that pre- and peri-natal insults to the lung can determine lung pathologies that are visible with CT scanning even years after the insult has occurred. These pathologies are associated with fixed airflow limitation early in life even in absence of cigarette smoke exposure.

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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.

 

Polverino F†, Stern DA, Snyder EM, Wheatley-Guy C, Bhatt SP, Martinez FD, erra S, Morgan WJ. Lower Respiratory Illnesses in Childhood are Associated with The Presence of Air Trapping in Early Adulthood. Resp. Med. 2023, PMID: 36508986.

 

Polverino F†, Washko GR, Covar RA, Hysinger EB, Hackett TL, Bhatt SP, Brusselle G, Dharmage SC. The low flyers: persistent airflow limitation in young adults. Lancet Respir Med. 2022 Jul 15:S2213-2600(22)00250-8.

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