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.
IMAGING
Immunohistochemistry, immunofluorescence, image 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 & MOLLECULAR 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
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.
Supporting Documents
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
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 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 Oct 1;202(7):1048-1051. PMID: 32479109
Pinto-Plata V, Casanova C, Divo M, Tesfaigzi Y, Calhoun V, Sui J, Priolo C, Polverino F, Petersen H, de-Torres JP, Marin JM, Owen C, Baz R, Cordoba-Lanus E, Celli B. Plasma Metabolomics and survival differences in COPD patients. Resp. Res 2019. Oct 15;20(1):219. PMID: 31615518
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 showed, by integrating radiomics and spatial transcriptomics and proteomics, that pulmonary lymphoid follicles from individuals with emphysema have a predominant autoimmune signature that is absent in COPD patients without emphysema.
Supporting Documents
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. PMID: 26073875
Polverino F, Baraldo S, Bazzan E, Agostini S, Turato G, Lunardi F, Balestro E, Damin M, Papi A, Maestrelli P, Calabrese F, 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
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. July 26 2019. PMID: 31348682
Rojas-Quintero J, Ochsner SA, New F, Divakar P, Yang CX, Wu TD, Robinson J, Chandrashekar DS, Banovich NE, Rosas IO, Sauler M, Kheradmand F, Gaggar A, Margaroli C, San Jose Estepar R, McKenna NJ, Polverino F. Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in COPD. Am J Resp Crit Care Med 2024. PMID: 38064378
New insights into COPD models and lung cancer
First, we have discovered the first protective proteinase in COPD: A Disintegrin and A Metalloproteinase Domain-8 (ADAM8), which protects the lung from CS-induced emphysema and mucus metaplasia. 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. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. We have identified a T cell immune signature in patients with COPD that renders them more susceptible to SARS-CoV 2-associated lung disease. 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.
Supporting Documents
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. PMID: 29750543
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. PMID: 25542772.
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
Polverino F†, Mirra D, Esposito R, Spaziano G, Sgambato M, Piegari E, Cozzolino A, Cione E, Gallelli L, Capuozzo A, 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 Dec 27;12(1):22402. PMID: 36575294
Pathogenesis of early airflow limitation
Chronic Obstructive Pulmonary Disease (COPD) is characterized by accelerated aging, driven mostly by cigarette smoke (CS)-derived oxidants. However, there is now evidence that pre- and peri-natal factors strongly contribute to what the lung function is going to be in an individual lifespan. Among these factors, pulmonary infections, prematurity, maternal smoke, childhood asthma, can determine low lung function starting from the first years of life. We have dissected some of these factors, and have explored how lung function impairment can be monitored using lung imaging starting from the early adulthood. We have analyzed the use of lung MRI in the diagnosis of early COPD in premature children and young adults. Similarly, we have assessed the influence of early-life determinant on the pathogenesis of chronic airflow limitation,and demonstrated that pre- and per-natal insults to the lung can determine lung pathologies that are visible with CT scanning even years after the insult has occurred.
Supporting Documents
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. PMID: 31954683
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. PMID: 35850124
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. PMID: 30114375
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.
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.
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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.