Fas/Fas Ligand-mediated Apoptosis Promotes Hypersensitivity Pneumonitis in Mice by Enhancing Maturation of Dendritic Cells

• Published in: American journal of respiratory and critical care medicine 2010-06, Vol.181 (11), p.1250-1261
• Main Authors: Hwang, Su Jin, Kim, Hye Sung, Chung, Doo Hyun
• Format: Article
• Language: English
• Subjects: Alveolitis, Extrinsic Allergic - pathology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antigens; Apoptosis; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Bronchoalveolar Lavage Fluid - cytology; Cytokines - metabolism; Dendritic cells; Dendritic Cells - cytology; Epithelial Cells - metabolism; Fas Ligand Protein - metabolism; Flow Cytometry; Granulocytes; Granulocytes - metabolism; Granulomas; Intensive care medicine; Killer Cells, Natural - metabolism; Labeling; Lavage; Ligands; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Proteins; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor necrosis factor-TNF
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200909-1337OC

Fas/Fas ligand (FasL)-mediated apoptosis has been implicated in various lung diseases, but whether Fas/FasL-mediated apoptosis in the lungs plays a critical role in the development of hypersensitivity pneumonitis (HP) is unclear. To explore the functional roles of Fas/FasL-mediated apoptosis in HP. Fas-deficient (lpr/lpr), FasL-deficient (gld/gld), and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally. lpr/lpr and gld/gld mice exhibited attenuation of HP in terms of histological alterations, influx of immune cells in bronchoalveolar lavage fluid (BALF), and SR-specific immune responses compared with B6 mice, similar to the effects of SR in B6 mice given a caspase inhibitor. The lungs of lpr/lpr and gld/gld mice showed high IL-4 production and low IFN-gamma, IL-8, macrophage inflammatory protein-2, IL-1beta, and tumor necrosis factor-alpha production compared with those of B6 mice. Moreover, mice with chimeric B6 and lpr/lpr bone marrow revealed that apoptosis of nonhematopoietic and BALF immune cells of the lungs enhanced immune responses against SR antigen. Gr-1(+) granulocytes in BALF expressed annexin V and their depletion in B6 mice attenuated HP. Apoptosis of nonhematopoietic cells and Gr-1(+) granulocytes in the lungs enhanced the maturation of pulmonary CD11c(+) dendritic cells and their production of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, resulting in recruitment of immune cells into the lungs during HP. These results suggest that apoptosis in nonhematopoietic cells and Gr-1(+) granulocytes of the lungs promotes HP by enhancing maturation and chemokine production of CD11c(+) dendritic cells.