| Chronic obstructive plumonary disease (COPD) is a common disease state characterized by airflow limitation that is progressive and not fully reversible. It is a major cause of chronic morbidity and mortality and currently the fourth leading cause of death throughout the world, and thus it becomes a major pulbic health problem. COPD is closely related to chronic bronchitis and emphysema. Emphysema shows abnormal and permanent dilatation of distal bronchioles going with destruction of alveolar walls and bronchioles while without fibrosis. However, the pathogenesis of emphysema keeps not completely clear. The construction of emphysematous animal model is helpful to open its pathogenesis. Lung volume reduction surgery (LVRS) is a burgeoning operation that ameliorates dyspnea and improves quality of life in selected patients with severe emphysema. Other researches mostly focus on clinical observation of lung parenchyma itself, respiratory muscles, chest wall and cardiovascular function. Whereas, there are few applied basic researches on LVRS. At the same time, many questions about LVRS are in issue. For example, which is the better procedure between unilateral versus bilateral LVRS? Does lobectomy of patients with severe emphysema belong to LVRS? How much lung parenchyma should be removed during LVRS in order to receive the best therapeutic effect? Moreover, there are few researches on changes of inflammation and structural remodeling of small airway after LVRS. This kind of surgical treatment is currently regarded as just a palliative operation for severe emphysema. Therefore, how to consolidate the therapeutic effect of LVRS and prevent the postoperative progress of emphysema has become new task and research hotspot in medical field. To interdict inflammatory response, reverse the airway remodeling and accelerate the repair of alveoli are very important to treatment of pulmonary emphysema. Many experimental and clinical researches on emphysema therapy with retinoic acid (RA) have recently performed. However, its therapeutic effect is not definite,and its mechanism keeps still unclear. And we didn't find any research report about the effect of RA on airway inflammation and remodeling of emphysema after LVRS.To investigate the effects of LVRS on pulmonary histology and small airway inflammation and the ati-inflammatory therapy of the small airway after LVRS, we focused on the therapeutic effect of LVRS on pulmonary emphysema to study the following four aspects: 1. Emphysematous animal models of rabbit were established by inhaling smog produced from cigarette, injecting papain through trachea and combination of the both previous ways respectively. The models were evaluated by means of high resolution CT, lung perfusion scintigraphy, arterial blood gas analysis, pulmonary function, pulmonary histology and alveolar morphology. We selected one animal model among them, which was effective, stable and analogous to mankind emphysema in order to meet the need of applied basic research on surgical treatment of emphysema such as LVRS. 2. Unilateral and bilateral LVRS and lobectomy were carried out in emphysematous rabbits. With the help of arterial blood gas analysis, pulmonary function, pathology and quantitative analysis of alveolar morphology, the therapeutic effect of LVRS with different resection volume of lung parenchyma on emphysema were investigated, especially on the changes of pulmonary function and alveolar morphology. And the effects of unilateral and bilateral LVRS and lobectomy on emphysema were compared. 3. The effects of bilateral LVRS on inflammation response and structural remodeling of small airway were evaluated by ways of histology with HE and Masson staining. 4. Protein and mRNA expression of inflammatory cytokines such as Interleukin (IL)-ip, IL-8, tumor necrosis factor (TNF)-a and transforming growth factor-betal (TGF-pl) in serum, bronchoalveolar lavage fluid (BALF) and pulmonary tissue were detected, by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, reverse transcriptive-polymerase chain reaction (RT-PCR) and Western blot. DNA bonding acitivity of transcription factors including nuclear factor-kappa B (NF- k B) and activator protein-1 (AP-1) through ectrophoretic mobility shift assay (EMSA). 5. The effects of all-trans-retinoic acid (ATRA) on small airway inflammation response, structural remodeling, inflammatory cytokine release and transcription factor activation after LVRS were primarily explored by the ways above.The main results and conclusion:1. Combination of passive smoking and papain instillation through trachea led todestruction of distal airway and alveoli, increase of airway resistance and decrease of effective gas exchange, and thus caused typical obstructive emphysema of airflow obstruction and pulmonary function impairment (PO.01). Moreover, the period of emphysema induction was obviously shortened by this combined means. Therefore, an experimental animal model of emphysema, which is analogous to mankind emphysema caused by long-term smoking, could be established by combination of passive smoking and papain instillation through trachea. This model might be used in experimental study about surgical treatment of emphysema such as LVRS.2. Pulmonary function and histology of emphysematous rabbits could not be improved by unilateral and bilateral sham operation and LVRS with small (12.5%) or large (37.5%) resection volume of lung parenchyma (/*>().05). Unilateral LVRS with appropriate volume (25%), lobectomy and bilateral LVRS might effectively ameliorate the pulmonary function and alveolar morphology (PO.05, P<0.05, PO.01). The therapeutic effect of bilateral LVRS on emphysema was better than that of unilateral one (P<0.05), and the effect of lobectomy is just like that of unilateral LVRS (P>0.05).3. Long-term chronic inflammation might result in a structural remodeling of the small airway wall, and ultimately brought on impaired pulmonary function in emphysematous rabbits (P<0.0l). Alveolar macrophages (AM) and polymorphonuclear cells (PMN) were predominately in the lumen of small airway, while AM and lymphocytes mainly lied in the airway wall (P<0.01). Obvious reversion of small airway inflammation and structural remodeling and improvement of pulmonary function could be achieved by LVRS (,P<0.01).4. The protein and mRNA expression of IL-ip, IL-8, TNF-a and TGF-(31 increased notablely in emphysematous rabbits (PO.01), which showed that the inflammation cytokines network above were concerned with the developing process of emphysema. The expression levels of IL-ip, IL-8, TNF-a and TGF-pi decreased markedly after LVRS in emphysematous rabbits (PO.01). The DNA bonding activity of NF- k B and AP-1 were enhanced in emphysematous rabbits (P<0.0l), which opened out that the transcription factors above were participated in the pathologic process of emphysema. The transcription activities of NF- k B and AP-1 were obviously weakened after LVRS CPO.01). This might be another cause which reversed the small airway inflammation and structural remodeling in emphysematous rabbits.5. Farther reversion of small airway inflammation and structural remodeling in emphysematous rabbits received LVRS was carried out by celiac injection of ATRA. The numbers of leukocytes, AM and PMN in BALF of emphysematous rabbits were reduced distinctly after LVRS (PO.05). The protein and mRNA expression levels of L-l 3 , IL-8, TNF- a and TGF- P 1 decreased markedly after LVRS in emphysematous rabbits (P<0.05). The transcription activity of NF- k B and AP-1 were obviously weakened after LVRS (PO.05). So, ATRA could improve the impaired pulmonary function after LVRS (TO.05).
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