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Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema Mimae T; Hagiyama M; Inoue T; Yoneshige A; Kato T; Okada M; Murakami Y; Ito AThorax 2014[Mar]; 69 (3): 223-31RATIONALE: Alveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), alphaCTF and betaCTF, through protease mediated ectodomain shedding. OBJECTIVE: To explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells. METHODS AND RESULTS: Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express alphaCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-alphaCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of alphaCTF. CONCLUSIONS: CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing alphaCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.|Alveolar Epithelial Cells/*metabolism/pathology[MESH]|Apoptosis/*immunology[MESH]|Biomarkers/metabolism[MESH]|Blotting, Western[MESH]|Cell Adhesion Molecule-1[MESH]|Cell Adhesion Molecules/immunology/*metabolism[MESH]|Humans[MESH]|Immunoglobulin Fragments/*metabolism[MESH]|Immunoglobulins/immunology/*metabolism[MESH]|In Situ Nick-End Labeling[MESH]|Intercellular Adhesion Molecule-1/metabolism[MESH]|Predictive Value of Tests[MESH]|Proteolysis[MESH]|Pulmonary Emphysema/*genetics/immunology/*pathology[MESH]|Risk Factors[MESH]|Sensitivity and Specificity[MESH]|Severity of Illness Index[MESH]|Smoking/adverse effects[MESH] |
