RICERCA ITALIANA     

TOBACCO SMOKE, INFLAMMATION AND LUNG CANCER: BIOLOGICAL, MOLECULAR, CLINICAL AND PATHOLOGICAL FEATURES.

Università degli Studi di Modena e Reggio Emilia

Abstract

Tobacco smoke is the main risk factor both for chronic obstructive pulmonary disease and for lung cancer in industrialized countries and its impact on these disease is progressively growing in developing countries too. Moreover, it is not only the common etiologic factor for these disease but chronic lung inflammation due to tobacco smoking, especially when associated with airflow limitation, may represent "per se" a predisposing condition for the onset of the tumor. The aim of this multicenter, multidisciplinary research program is the study of biological and molecular modifications induced by tobacco smoke on pulmonary tissues and cells, and the "in vivo" evaluation of the corresponding changes at the clinical and pathological level.
Overall, the program involves seven Research Units. Some of them will conduct mainly experimental studies with cell biology, molecular biology or molecular genetics techniques, whose results may be subsequently used for interpreting the "in vivo" data obtained by the clinical Research Units. The potential associations between inflammation and lung cancer will be searched for and analysed within each project, when possible. Each single project has a clearly defined purpose which is intrinsically able to provide original results. However, the multidisciplinary structure of the research program, which represents its most original feature, among Units having the effects of tobacco smoke on human lung as the common target will be able to >>>

Principal Investigator

Leonardo FABBRI Università degli Studi di MODENA e REGGIO EMILIA

Research Objectives

Tobacco smoke is the main risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer in Western countries, the incidence of morbidity and mortality for both progressively increasing. Moreover, if cigarette smoke is on one hand the common etiologic factor for these two diseases, chronic lung inflammation, especially when associated to airflow limitation, is a predisposing factor for lung cancer itself. The complex molecular and biological mechanisms which play a role in this pro-neoplastic action of lung inflammation are largely unknown, but they probably involve many different pathophysiologic pathways such as oxidative stress, tissue remodelling, cell proliferation and apoptosis, etc.
The aim of this interdisciplinary research program is the study of molecular and biological modifications induced by tobacco smoke on lung tissues and cells, both as favouring inflammation and carcinogenesis, and the "in vivo" evaluation of their clinical and pathological evidence. The program involves seven Research Units. In the part regarding "in vitro" studies the different Reseacrh Units will use corroborative analytical techniques (cell biology, molecular biology, molecular genetics) which allow the study of the role of chemokines and of chemokines decoy receptors in lung inflammatory disorders, the analysis of tissue expression of different isoforms of clusterin in lung inflammatory and neoplastic diseases, the gene expression profile of human bronchial >>>

First Results

Definition of experimental protocols, generation of cell lines, accurate stting-up of the methodologies for preparation of study reagents.
Distribution of duties to different Units.
Definition of selection criteria (inclusion and exclusion)for study populations.In this second phase, the research Units will evaluate the expression of the activation molecules in study in plasmids, cell lines, biopsies and bronchoalveolar lavage samples.
Furthermore, we will analyze the responses of cell lines following stimulation by cigarette smoke, environmental preparation and extracts of viruses.
The role and the characterization of T lymphocytes involved in the pathogenesis of COPD and lung cancer will be analyzed in cell lines and biopsies.
The parameters of inflammatory cellular activation will be measured in patients selected based upon the criteria established during the previous phase.
The parameters for the discriminant analysis of patients with prevalent emphysema or prevalent bronchitis will be applied to a prospective cohort of patients.In this last phase of the project the data obtained in vitro will be collected and statistically analyzed.
These data will then be correlated with the clinical data of the patients from whom biopsies have been obtained. the results will be correlated mainly with severity of disease, survival and response to therapies.
The genetic data will be compared to those already available in public >>>

Timescale

24 months

National and international background

Tobacco smoke represents the main risk factor for death, and causes a number of different diseases. In many developing countries the mortality due to diseases related to tobacco smoke is steadily increasing. It has been calculated that in year 2000 almost 5 million of premature deaths have been caused by cigarette smoke and of these almost 2 million were due to either chronic obstructive pulmonary disease (COPD) or lung cancer (1). Future perspectives for the forthcoming years consider a further increase in the incidence of these smoke-related events (2). Tobacco smoke can directly cause inflammation and tissue remodeling in the lungs of smokers (3). These effects are due, at least in part, to the oxidative stress induced by the smoke itself; the maintenance of the pulmonary oxidative processes is due both to the oxidants present in the cigarette smoke and to the elicited immune response (4). Cigarette smoke contains a large quantity of strong oxidants and increases the endogenous production of reactive oxygen species (ROS) by respiratory cells, in particular alveolar macrophages and neutrophils (5), the main sources of ROS. The final net result of these events is the generation of self-maintaining circuits, which can maintain and amplify the inflammatory processes associated with COPD, through paracrine and/or autocrine mechanisms.
Experimental evidence proves that cigarette smoke, the main risk factor for COPD, is one of the most important among the causes of the >>>