**1. Introduction**

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Small Interfering RNA Targeting Heme Oxygenase-1 Enhances Ischemia-Reperfusion-induced Lung Apoptosis *J. Biol. Chem.* Vol.279 No.(11): pp.10677-10684 The pulmonary diseases of obstructive character have high prevalence in the human population and has been subject of several clinical and experimental studies in order to seek a wider understanding of their pathogeny, physiopathology and, especially, the establishment of more rational ways for their treatment. Accordingly, this great effort has led to an extraordinary widening in the concepts of obstructive diseases in the last years, involving the integration of mechanical factors, inflammatory agents, autonomic regulation of airways and environmental aspects.

The COPD may be understood as a pathologic condition in which a non-reversible and limited gas exchange occurs. There are two clinical entities that constitute the COPD: chronic bronchitis and emphysema. Within the COPD spectrum, the main characteristic of pulmonary emphysema is air flow blockage and progressive dyspnea, arising out of the impairment of alveolar walls and increase of air spaces distal to terminal bronchiole, without significant pulmonary fibrosis (Barnes et al., 2003; GOLD, 2009; Oliveira et al., 2000).

The oxidative damage to which lungs are submitted to, as well as the inflammation occurring as a response to irritant agents, such as those coming from air pollution and cigarette smoke, contributes to the induction of the pulmonary degeneration (Lee et al., 2011). Therefore, it may be concluded that chief characteristic of COPD is the acceleration of functional and morphologic loss, with limitation of gas exchanges, resulting in progressive dyspnea, disability and premature death.

Therefore, the development and progression of the pathology are resulting from the interaction of genetic and environmental factors (Ribeiro-Paes et al., 2009). About 1-3% of cases of emphysema are generated by enzyme α1-antitrypsin deficiency, that characterizes a genetic abnormality as an inheritance of autossomal recessive pattern. The other risk factors include: age, infections, as well as social and economic factors (Mannino & Buist, 2007).

Smoking, however, has been established as the major cause related with COPD, resulting for active or passive exposure to the cigarette smoke, and corresponds to 15-20% of cases of

Cell Therapy in Chronic Obstructive Pulmonary Disease: State of the Art and Perspectives 457

physiopathological mechanisms involved in the formation of the emphysema. Up to the beginning of the 80's decade, the studies involving induced pulmonary emphysema in animals by exposure to cigarette smoke were scarce and their reliability questioned (March, 2000). In 1981, Huber and coworkers proposed a study based on the model of induced emphysema through exposure to cigarette smoke. Some achieved results in the study, with respect to morphometric and physiological aspects provided the basis for the ensuing research. According to the report from the First Siena International Conference on Animal Models of COPD held at the University of Siena in 2001, the induced lesions with the use of this model are similar to those observed in emphysematous humans, highlighting the importance of the stimulus through cigarette smoke in COPD experimental models. (Hele,

At our laboratory, a new apparatus (Figure 1) for induced emphysema through exposure to cigarette smoke is under test. The present device has a series of innovations when compared to the already existing inhaling models, such as the fact that the animals are contained inside acrylic containers making up the device, while in other cages the animals stay freed. Another important aspect worth highlighting relates to the smoke, which is pumped inside the box. In the device created by our team, the smoke pumped into the box interior comes from puffing on the cigarette; therefore, the situation of an active smoking human is mimicked. This apparatus is expected to lead to a model which mimics, as close as possible, the human pathology and, accordingly, which can be applied to research projects oriented to the analysis of physiopathological processes and to the development of new therapies in

Fig. 1. Apparatus created by the team of the Laboratory of Genetics and Cell Therapy –

Notwithstanding the challenges involved in some parameters related to the cigarette-smokeinduced emphysema models, mainly with respect to the age of the animals, exposure time and reproducibility difficulty due to the required resources and time, this is a promising approach to turning animal models closer to the human, chiefly in relation to the physiopathological processes featured in the human pulmonary emphysema (March, 2000).

2001).

chronic degenerative pulmonary diseases.

GenTe Cel to induce emphysema by cigarette smoke.

pulmonary emphysema (Ribeiro-Paes et al., 2009). The cigarette smoke in their gas and particle stages has a significant quantity of oxidant substances. A high number of particles and oxidant agents are contained in cigarette smoke. Oxidant agents are capable of reducing the effect of the anti-protease system through the oxidation of the active site of those enzymes and leading to a direct injury to the extracellular matrix (Barnes 2000; Barnes et al., 2003; Bast et al., 1991; Rufino & Lapa e Silva, 2006).

The Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2009) has pointed out COPD as a serious public health issue. The pathology is considered the fifth largest cause of death worldwide, and has 210 million patients, with 80 million already in the moderate and/or serious stage of the disease. Estimates put it at the third ranking of cause of death in 2020 (GOLD, 2009; WHO, 2008). Moreover, faced with the ageing of world population, the economic burden of COPD should represent a significant parcel of the future global investments in health (Mannino & Buist, 2007).

Several clinical strategies, associated with the pulmonary rehabilitation techniques have contributed to the extension and improvement of the quality of life of emphysema patients. Notwithstanding the significant advances resulting from the introduction of new therapeutic approaches and rehabilitation, there has not been any efficient form of treatment up to now, other than the one in the palliative scope. The surgery treatment entails highly complex procedures and, in the specific case of lung transplant, a shortage of donors. By taking these aspects into account, experimental models have been proposed, in order to advance the knowledge about the physiopathological processes and new therapeutic approaches to the pulmonary emphysema (Gross et al., 1965; Hele, 2002; Mahadeva & Shapiro, 2002; Martorana et al., 1989; Nikula et al., 2000; Ribeiro-Paes et al., 2009).
