title: Neutrophil elastase induces MUC5AC secretion via protease-activated receptor 2.
abstract: Mucus hypersecretion is a major manifestation in patients with chronic inflammatory airway diseases, and mucin5AC (MUC5AC) protein is a major component of airway mucus. Previous studies have demonstrated that neutrophil elastase (NE) stimulates the secretion of MUC5AC from airway epithelial cells, however, the mechanism is poorly understood. NE is a known ligand for protein active receptors (PARs), which have been confirmed to participate in releasing MUC5AC in the airways. However, the role of PARs in NE-induced MUC5AC secretion remains unclear. We demonstrated that airway goblet-like Calu-3 cells express PAR1, PAR2, and PAR3 with a predominant level of PAR2. NE can increase PAR2 expression and MUC5AC release. In our study, we showed that NE binding to PAR2 can increase the cytosolic calcium concentration and subsequently activate PKC, leading to MUC5AC secretion. In order to investigate the mechanism of increased cytosolic calcium in Calu-3 cells, thapsigargin was used to exhaust the endoplasmic reticulum (ER) calcium pools, and 2-aminoethoxydiphenyl borate was used to inhibit the function of the store-operated calcium entry (SOCE) channels in the plasma membrane. We found that the NE-induced increase in intracellular calcium concentration is derived from release of the ER calcium pool and its subsequent calcium internal flux from the extracellular space via SOCE channels, which is dependent on sufficient levels of extracellular calcium.
authors: Division of Respiratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong District, Chongqing, China. joelle_zhou@163.com
authors: Jia
authors: J
authors: Zhou
authors: Juliy M
authors: JM
authors: Perelman
authors: Victor P
authors: VP
authors: Kolosov
authors: Xiangdong
authors: X
authors: Zhou
mesh_terms: D053119:Benzophenanthridines / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002614:Chelating Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000201:enzymology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D019272:Leukocyte Elastase / Q000502:physiology*; D055271:Mucin 5AC / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D053119:Benzophenanthridines; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D004791:Enzyme Inhibitors; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D010879:Piperazines; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D004533:Egtazic Acid; D019284:Thapsigargin; C016299:chelerythrine; C109986:2-aminoethoxydiphenyl borate; D011493:Protein Kinase C; D019272:Leukocyte Elastase; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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