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International Patent Classification
  • HUMAN NECESSITIES
    • MEDICAL OR VETERINARY SCIENCE; HYGIENE
      • PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES (bringing into special physical form A61J [N: mechanical aspects]; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; compounds per se C01, C07, C08, C12N; soap compositions C11D; micro-organisms per se C12N) [C0203]
    • TOBACCO; CIGARS; CIGARETTES; SMOKERS\' REQUISITES
      • CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
      • SMOKERS\' REQUISITES; MATCH BOXES (lighters F23Q)
Geographical classification
Bibliografia
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3. Croxton TL, Weinmann GG, Senior RM, Wise RA, Crapo JD, Buist AS. Clinical research in chronic obstructive pulmonary disease: needs and opportunities. Am J Respir Crit Care Med 2003; 167: 1142-1149.
4. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364:709721.
5. Laennec RTH. A treatise on the disease of the chest and on mediate auscultation. Philadelphia: Desilver, Thomas; 1835.
6. Saetta M, Turato .G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic ostructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1304-1309.
7. Peto R, Speizer FE, Cochrane AL, Moore F, Fletcher CM, Tinker CM, Higgins IT, Gray RG, Richards SM, Gilliland J, Norman-Smith B. The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation. Am Rev Respir Dis. 1983;128:491-500.
8. Vestbo J and Lange P Can GOLD Stage 0 Provide Information of Prognostic Value in Chronic Obstructive Pulmonary Disease? Am J Respir Crit Care Med. 2002;166:329-32.
9. Vestbo J, Prescott E, Lange P, and the Copenhagen City Heart Study Group. Association between chronic mucus hypersecretion with FEV1 decline and COPD morbidity. Am J Respir Crit Care Med 1996; 153:1530–1535.
10.Burrows B, Fletcher CM, Heard BE, Jones NL, Wootliff JS. The emphysematous and bronchial types of chronic airways obstruction. A clinicopathological study of patients in London and Chicago. Lancet 1966;1: 830-835.
11. Boschetto P, Miniati M, Miotto D, Braccioni F, De Rosa E, Bononi I, Papi A, Saetta M, Fabbri LM, Mapp CE. Predominant emphysema phenotype in chronic obstructive pulmonary. Eur Respir J 2003;21: 450-454.
12. Hashimoto S, Kobayashi A, Kooguchi K, Kitamura Y, Onodera H, Nakajima H. Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161: 237-243.
13. Orlandi I, Moroni C, Camiciottoli G, Bartolucci M, Pistolesi M, Villari N, Mascalchi M. Chronic obstructive pulmonary disease: thin-section CT measurement of airway wall thickness and lung attenuation. Radiology. 2005; 234:604-10.
14. Elkington PTF and Friedland JS. Matrix Metalloproteinases in destructive pulmonary pathology. Thorax 2006; 61, 259-66.
15. Lopez-Otin C, Overall C.M. Protease degradomics: a new challenge for proteomics. Nat. Rev. Mol. Cell Biol 2002; 3, 509–519.
16. Finlay G.A., Russell K.J., McMahon K.J., Darcy E.M., Masterson J.B., FitzGerald M.Z., OConnor C.M. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997; 52, 502–506.
17. Ohnishi K., Takagi M., Kurokawa Y., Satomi S., Konttinen Y.T. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab. Invest. 1998; 78, 1077–1087.
18. Cataldo D., Munaut C., Noel A., Frankenne F., Bartsch P., Foidart J.M., Louis R. MMP-2-and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int. Arch. Allergy Immunol. 2000; 123, 259–267.
19. Vignola A.M., Riccobono L., Mirabella A., Profita M., Chanez P., Bellia V., Mautino G., D'Accardi P., Bousquet J., Bonsignore G. Sputum metalloproteinase-9 tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 1998; 158, 1945–1950.
20. Bracke Ken, Cataldo D., Maes T., Gueders M., Noel A., Foidart J.M., Brusselle G., Pauwels R. Matrix metalloproteinase-12 expression in pulmonary dendritic cells of cigarette smoke exposed mice. Int. Arch. All. Immunol. 2005; 138, 169–179.
21. Hautamaki R.D., Kobayashi D.K., Senior R.M., Shapiro S.D. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 1997; 277, 2002–2004.
22. Hirsch J, Hansen KC, Burlingame AL, Matthay MA. Proteomics: current techniques and potential applications to lung diseases. Am J Physiol Lung Cell Mol Physiol 2004; 287: L1-L23.
23 Calabrese F, Giacometti C, Beghe B, Rea F, Loy M, Zuin R, Marulli G, Baraldo S, Saetta M, Valente M. Marked alveolar apoptosis/proliferation imbalance in end-stage emphysema.Respir Res. 2005; 10; 6:1 4.
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Keywords
COPD, EMPHYSEMA, PROTEASES, LUNG IMAGING, MOLECULAR AND ULTRASTRUCTURAL STUDY

Pathogenetic mechanisms and clinical manifestations of chronic obstructive pulmonary disease

Università degli Studi di Padova
Abstract
In industrialised countries, chronic obstructive pulmonary disease (COPD) is one of the most important causes of invalidity and mortality and its prevalence is increasing as compared to cardiovascular diseases and cancer. Epidemiological data estimates that by 2020, COPD will rank among the five most common causes of disability worldwide with consequent social and economic impact. COPD is defined as a disease state characterised by not fully reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, in particular to cigarette smoke. Indeed, cigarette smoke is the major risk factor for the development of COPD. However, only a minority of smokers develop COPD suggesting that additional factors related to the individual or to the environment might be involved in determining individual’s susceptibility to develop the disease. Despite the numerous studies which have endeavored to identify these factors, the pathogenetic mechanisms of COPD are still unknown.
The aim of this project is to identify specific etiopathogenetic factors which may influence the clinical course of COPD (in patients exposed to the same risk factors). Further aims are to investigate the cellular and molecular mechanisms involved in the pathogenesis and in the progression of chronic airflow limitation, focussing in particular on those involved in the parenchymal destruction that characterizes >>>

Principal Investigator
Marina Saetta Università degli Studi di PADOVA
Research Objectives
COPD is a progressive disease that may become extremely serious and disabling. Presently, in fact, COPD is one of most important causes of invalidity and mortality, and its prevalence is increasing as compared to cardiovascular diseases and cancer. COPD is not a disease entity, but rather a complex of conditions that include emphysema and chronic bronchitis. Even if cigarette smoking is the most important risk factor for the development of COPD, only 15 % of heavy smokers develop the disease, suggesting the presence of factors predisposing to the "susceptibility" to COPD. The pathogenetic mechanisms of the airflow limitation that characterizes COPD are still unknown, even if they have been the object of several studies in recent years. The aim of this project is to identify morphologic alterations and specific etiopathogenetic factors which may influence the clinical course of COPD (in patients exposed to the same risk factors). Further aims are to investigate the cellular and molecular mechanisms involved in the pathogenesis and in the progression of chronic airflow limitation, focussing in particular on those involved in the parenchymal destruction that characterizes emphysema. Finally, the correlations between cellular changes and clinical and functional parameters will be analysed in the different clinical phenotypes of the disease: “predominant emphysema”, “predominant bronchitis”, in different stages of severity and, in particular, severe COPD requiring lung >>>

Timescale
24 months
National and international background
According to the most recent guidelines, COPD is defined as a disease state characterised by not fully reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, in particular to cigarette smoke. Although COPD mainly affects the lungs, it also produces significant systemic consequences (1). Clinically, the principle symptoms of COPD are cough, sputum production and dyspnea. Furthermore, the natural history of the disease is marked by frequent exacerbation associated with infection, which can play an important role in the decline of lung function. The GOLD Guidelines classifies COPD into 5 stages, from 0 to 4, based on the severity of bronchoconstriction (1).
COPD is one of the major causes of invalidity and mortality in industrialised countries and its prevalence is increasing as compared to cardiovascular diseases and cancer. Epidemiological data estimates that by 2020, COPD will rank among the five most common causes of disability worldwide with consequent social and economic impact (2).
Cigarette smoking is the major risk factor for the development of COPD. However, since in a population of heavy smokers, only 15% of subjects develop COPD, it is possible that additional factors might be involved in determining individual's susceptibility to develop airflow limitation. These include genetic predisposition or environmental conditions (viral and bacterial >>>