Elucidating the dynamics and role of macrophages in a murine model of elastase-induced emphysema

macrophage;emphysema;chronic obstructive pulmonary disease;immunology;alveolar macrophage;Immunology

Poupore, Amy KathrynScott, Alan L. ;

Johns Hopkins University

关键词: macrophage;    emphysema;    chronic obstructive pulmonary disease;    immunology;    alveolar macrophage;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39485/POUPORE-THESIS-2016.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Emphysema is a complex immunological disease characterized by progressive and irreversible damage to the parenchymal lung tissue. While the cause of the disease can most often be attributed to habitual cigarette smoking or long-term exposure to other toxic substances, the underlying mechanisms of the pathogenesis are poorly understood. Of particular interest is why alveolar destruction continues to occur even after cessation of smoking. Data from human patient samples and laboratory animals have implicated a role for macrophages as they are a long-lived, abundant cell within the alveolar space that has the ability to secrete many of the damaging enzymes associated with tissue destruction. The importance of macrophages and their dynamics in the progression of emphysema are not, however, well understood. This work seeks to delineate the early myeloid cell dynamics in a murine elastase-induced emphysema model and to address the hypothesis that the early alterations in lung macrophage phenotype contribute to the progression of tissue destruction in this model.To elucidate the dynamics of macrophages, monocytes, and neutrophils in the lung, BALB/cJ mice were administered 3 enzymatic units of porcine pancreatic elastase and their lungs were analyzed via flow cytometry at various time points throughout the two-weeks following elastase administration. To evaluate the importance of lung macrophages during the acute period following elastase administration, macrophages were depletion by giving a total of three doses of clodronate-loaded liposomes. The effect of depletion on emphysema severity was determined by performing pulmonary function tests 21 days post-elastase.As expected, neutrophils and monocytes infiltrated the lung during the acute inflammatory phase, peaked around day 2 and 4, respectively, and returned to baseline by day 14 post-elastase. Resident alveolar macrophages underwent an initial contraction, followed by a slight proliferation, and by day 14 there were marginally fewer cells than in the naïve lung. Interstitial macrophages on the other hand proliferated and peaked by day 4 post-elastase and gradually declined to be somewhat elevated above baseline. Pulmonary function tests revealed that the depletion of macrophages worsened emphysema severity. This work supports the hypothesis that macrophages play a significant role in emphysema progression, however it does not address the mechanism of action. Future research using macrophage reprogramming may help address this.