Person: Polverino, Francesca
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Polverino
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Francesca
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Polverino, Francesca
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Publication Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring(BioMed Central, 2015) Lao, Taotao; Glass, Kimberly; Qiu, Weiliang; Polverino, Francesca; Gupta, Kushagra; Morrow, Jarrett; Mancini, John Dominic; Vuong, Linh; Perrella, Mark; Hersh, Craig; Owen, Caroline; Quackenbush, John; Yuan, Guo-Cheng; Silverman, Edwin; Zhou, XiaoboBackground: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. Methods: We exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. Results: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/-mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. Conclusions: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0137-3) contains supplementary material, which is available to authorized users.Publication Mononuclear Phagocytes and Airway Epithelial Cells: Novel Sources of Matrix Metalloproteinase-8 (MMP-8) in Patients with Idiopathic Pulmonary Fibrosis(Public Library of Science, 2014) Craig, V; Polverino, Francesca; Laucho-Contreras, Maria E.; Shi, Yuanyuan; Liu, Yushi; Osorio, Juan C.; Tesfaigzi, Yohannes; Pinto-Plata, Victor Manuel; Gochuico, Bernadette R.; Rosas, Ivan; Owen, CarolineObjectives: Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps. Methods: We measured MMP-8 levels and forms in blood and lung samples from IPF patients versus controls using ELISAs, western blotting, and qPCR, and assessed whether MMP-8 plasma levels in 73 IPF patients correlate with rate of lung function decline and mortality. We used immunostaining to localize MMP-8 expression in IPF lungs. We quantified MMP-8 levels and forms in blood leukocytes from IPF patients versus controls. Results: IPF patients have increased BALF, whole lung, and plasma levels of soluble MMP-8 protein. Active MMP-8 is the main form elevated in IPF lungs. MMP-8 mRNA levels are increased in monocytes from IPF patients, but IPF patients and controls have similar levels of MMP-8 in PMNs. Surprisingly, macrophages and airway epithelial cells are the main cells expressing MMP-8 in IPF lungs. Plasma and BALF MMP-8 levels do not correlate with decline in lung function and/or mortality in IPF patients. Conclusion: Blood and lung MMP-8 levels are increased in IPF patients. Active MMP-8 is the main form elevated in IPF lungs. Surprisingly, blood monocytes, lung macrophages, and airway epithelial cells are the main cells in which MMP-8 is upregulated in IPF patients. Plasma and BALF MMP-8 levels are unlikely to serve as a prognostic biomarker for IPF patients. These results provide new information about the expression patterns of MMP-8 in IPF patients.Publication Idiopathic pulmonary fibrosis and coronary artery disease(BioMed Central, 2014) Cicchitto, Gaetano; Musella, Valentina; Acitorio, Maria; Capuano, Nicola; Fiorenzano, Giuseppe; Owen, Caroline; Polverino, Mario; Polverino, FrancescaIdiopathic pulmonary fibrosis (IPF) is defined as a chronic fibrosing interstitial disease of unknown cause, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP); it generally progresses into respiratory failure and death. Although progression of the disease is the most common cause of death, there are increasing reports of its association with other pathologies has been reported: e.g., IPF patients seem more susceptible to cardiovascular diseases. Therefore, other pathologies might also influence the natural course. In this paper, we describe a case of IPF and coronary artery disease (CAD). We emphasize the importance of cardiopulmonary exercise test (CPET) as a useful procedure to monitor disease progression in IPF patients. We also stress the importance of a careful analysis of variables measured for an accurate interpretation of the clinical picture and an improvement of the clinical management of patients. Moreover, we suggest that a careful assessment of CPET parameters may additionally help in the early detection of high cardiovascular ischemic risk.Publication Effects of sex hormones on bronchial reactivity during the menstrual cycle(BioMed Central, 2014) Matteis, Maria; Polverino, Francesca; Spaziano, Giuseppe; Roviezzo, Fiorentina; Santoriello, Carlo; Sullo, Nikol; Bucci, Maria Rosaria; Rossi, Francesco; Polverino, Mario; Owen, Caroline; D’Agostino, BrunoBackground: Many asthmatic women complain of symptom exacerbations in particular periods, i.e. during pregnancy and menstrual cycles (perimenstrual asthma: PMA)". The goal of this study was to study the effect of the luteal and follicular phases of the menstrual cycle on bronchial reactivity (BR) in a group of asthmatic women. Methods: For this purpose, 36 pre-menopausal women were enrolled and underwent testing for resting pulmonary function, measurement of the diffusing capacity of the lung for carbon monoxide (DLCO), and airway responsiveness to methacholine in the follicular and luteal phases of their menstrual cycles. We also measured plasma hormone levels and levels of cyclic adenosine monophosphate (cAMP; a mediator of bronchial smooth muscle contraction) and testosterone in induced sputum samples. Results: Our study showed that about 30% of the asthmatic women had decreased PC20FEV1.0 in the follicular phase of menstrual cycle with a significant correlation between PC20FEV1.0 and serum testosterone levels. Moreover, marked increases in sputum testosterone levels (mean = 2.6-fold increase) together with significant increases in sputum cAMP concentrations (mean = 3.6-fold increases) were observed during the luteal phase of asthmatic patients, suggesting that testosterone contributes to the pathophysiology of PMA. We excluded the possibility that testosterone directly inhibits phosphodiesterase (PDE) activity as incubating PDE with testosterone in vitro did not reduce PDE catalytic activity. Conclusions: In conclusion, our data show that PC20FEV1.0 was decreased in the follicular phase of the menstrual cycle in about 30% of women and was associated with lower cAMP levels in sputum samples, which may contribute to bronchoconstriction. Our results also suggest a link between PMA and testosterone levels. However, whether these findings are of clinical significance in terms of the management of asthma or asthma worsening during the menstrual cycle needs further investigation.Publication Juniors’ voice at the ERS International Congress, Amsterdam 2015: Juniors’ voice(European Respiratory Society, 2015) Polverino, Francesca; Longhini, Federico; Vanaudenaerde, Bart; Bikov, Andras; Aamli, Ane; Singanayagam, Aran; Kahn, Nicolas; Boots, Agnes; Skoczynski, SzymonPublication Adam8 Limits the Development of Allergic Airway Inflammation in Mice(The American Association of Immunologists, 2013) Knolle, M. D.; Nakajima, T.; Hergrueter, A.; Gupta, K.; Polverino, Francesca; Craig, V; Fyfe, S. E.; Zahid, M.; Permaul, Perdita; Cernadas, Manuela; Montano, Giancarlo Vengco; Tesfaigzi, Y.; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, CarolineTo determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma.Publication Acid–base balance, serum electrolytes and need for non-invasive ventilation in patients with hypercapnic acute exacerbation of chronic obstructive pulmonary disease admitted to an internal medicine ward(BioMed Central, 2016) Schiavo, Alfonso; Renis, Maurizio; Polverino, Mario; Iannuzzi, Arcangelo; Polverino, FrancescaBackground: Hypoventilation produces or worsens respiratory acidosis in patients with hypercapnia due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In these patients acid–base and hydroelectrolite balance are closely related. Aim of the present study was to evaluate acid–base and hydroelectrolite alterations in these subjects and the effect of non-invasive ventilation and pharmacological treatment. Methods: We retrospectively analysed 110 patients consecutively admitted to the Internal Medicine ward of Cava de’ Tirreni Hospital for acute exacerbation of hypercapnic chronic obstructive pulmonary disease. On admission all patients received oxygen with a Venturi mask to maintain arterial oxygen saturation at least >90 %, and received appropriate pharmacological treatment. Non-Invasive Ventilation (NIV) was started when, despite optimal therapy, patients had severe dyspnea, increased work of breathing and respiratory acidosis. Based on Arterial Blood Gas (ABG) data, we divided the 110 patients in 3 groups: A = 51 patients with compensated respiratory acidosis; B = 36 patients with respiratory acidosis + metabolic alkalosis; and C = 23 patients with respiratory acidosis + metabolic acidosis. 55 patients received only conventional therapy and 55 had conventional therapy plus NIV. Results: The use of NIV support was lower in the patients belonging to group B than in those belonging to group A and C (25 %, vs 47 % and 96 % respectively; p < 0.01). A statistically significant association was found between pCO2 values and serum chloride concentrations both in the entire cohort and in the three separate groups. Conclusions: Our study shows that in hypercapnic respiratory acidosis due to AECOPD, differently from previous studies, the metabolic alkalosis is not a negative prognostic factor neither determines greater NIV support need, whereas the metabolic acidosis in addition to respiratory acidosis is an unfavourable element, since it determines an increased need of NIV and invasive mechanical ventilation support.Publication Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice(2015) Cloonan, Suzanne M.; Glass, Kimberly; Laucho-Contreras, Maria E.; Bhashyam, Abhiram; Cervo, Morgan; Pabón, Maria A.; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I.; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C.; Parameswaran, Harikrishnan; Williams, Niamh C.; Rooney, Kristen T.; Chen, Zhi-Hua; Goldklang, Monica P.; Yuan, Guo-Cheng; Moore, Stephen; Demeo, Dawn; Rouault, Tracey A.; D’Armiento, Jeanine M.; Schon, Eric A.; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin; Owen, Caroline; Choi, Augustine M.K.Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.Publication 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?(BioMed Central, 2016) Polverino, Francesca; Laucho-Contreras, Maria; Rojas Quintero, Joselyn; Divo, Miguel; Pinto-Plata, Victor; Sholl, Lynette; de-Torres, Juan P.; Celli, Bartolome; Owen, CarolineBackground: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an excessive activation of the adaptive immune system and, in particular, uncontrolled expansion of the B-cell pool. One of the key promoters of B cell expansion is A PRoliferation-Inducing Ligand (APRIL). APRIL has been strongly linked to non small cell lung cancer (NSCLC) onset and progression previously. However, little is known about the expression of APRIL in the lungs of COPD patients. Methods: Using immuno-fluorescence staining, the expression of APRIL was assessed in sections of lungs from 4 subjects with primary diagnosis of COPD (FEV1 33 ± 20 % predicted), 4 subjects with primary diagnosis of NSCLC, 4 subjects diagnosed with both COPD and NSCLC, smokers without COPD or NSCLC and 3 healthy never-smokers. The percentage of B cells, alveolar macrophages (AMs) and polymorphonuclear neutrophils (PMNs) in the lung and alveolar epithelial cells (AECs) that stained positively for APRIL was quantified using epi-fluorescence microscopy and image analysis software. Results: The percentage of APRIL-expressing B cells, AMs, PMNs and alveolar epithelial cells (AECs) was higher in patients having both COPD and NSCLC than in patients with either COPD or NSCLC alone, SC or NSC (p < 0.03 for all comparisons). The percentage of APRIL-expressing AMs and AECs (but not in B cells) was higher in patients with NSCLC alone than in patients with COPD alone. The percentage of APRIL-expressing AECs (but not B cells or AMs) was higher in COPD patients than in SC and NSC (p < 0.05 for all comparisons). The percentage of APRIL-expressing B cells, AMs and AECs cells was similar in NSC and SC. Conclusion: The percentage of APRIL-expressing B cells, AMs and AECs is higher in the lungs of patients with both COPD and NSCLC than in patients with COPD or NSCLC alone or control subjects. These findings suggest that APRIL may contribute to the pathogenesis of both COPD and NSCLC, and possibly to the development of NSCLC in patients with established COPD.Publication Anatomy and neuro-pathophysiology of the cough reflex arc(BioMed Central, 2012) Polverino, Mario; Fasolino, Marco; Andò, Filippo; Alfieri, Antonio; De Blasio, Francesco; Polverino, FrancescaCoughing is an important defensive reflex that occurs through the stimulation of a complex reflex arc. It accounts for a significant number of consultations both at the level of general practitioner and of respiratory specialists. In this review we first analyze the cough reflex under normal conditions; then we analyze the anatomy and the neuro-pathophysiology of the cough reflex arc. The aim of this review is to provide the anatomic and pathophysiologic elements of evaluation of the complex and multiple etiologies of cough.