The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction. The main risk factor for developing COPD is cigarette smoking; however, only about 20% of smokers develop lung disease. The mechanisms by which cigarette smoke leads to pathological changes in both airways and lung parenchyma are unclear. Pulmonary inflammation, localized to the airways, is a pathological feature in the lungs of COPD patients. A predominance of macrophages and CD8 ϩ T lymphocytes are found both in bronchial biopsies (43,44) and in the lung parenchyma at sites of parenchymal destruction (29). These findings suggest that CD8 ϩ T lymphocytes may be responsible for damage to the lung, either by directly injuring neighboring cells, by secreting molecules that injure the lung, or by recruiting and activating additional inflammatory cells.The stimuli responsible for triggering inflammation are not known, but infectious pathogens likely play a role in the initiation or perpetuation of pulmonary inflammation in COPD. Much of the work examining the role of infection in the course and pathogenesis of COPD has focused on bacterial colonization (45), but bacterial or viral colonization may be insufficient to explain pathogenesis. An intriguing alternate pathogen that has received recent attention is the fungus Pneumocystis jirovecii. Although it was previously thought to be an opportunistic pathogen that caused serious pneumonia only in severely immunocompromised patients, recent investigations substantiate the exi...

No abstract

No abstract