Phosphatidylinositol 3-kinases pathway mediates lung caspase-1 activation and high mobility group box 1 production in a toluene-diisocyanate induced murine asthma model.
We have previously demonstrated that downregulating HMGB1 decreases airway neutrophil inflammation in a toluene-diisocyanate (TDI)-induced murine asthma model, yet how HMGB1 is regulated in the lung remains uncertain. In this study, we intended to explore whether PI3K signaling pathway mediates pulmonary HMGB1 production in TDI-induced asthma model and the possible roles of NLRP3 inflammasome and caspase-1 in this process. BALB/c mice were sensitized and challenged with TDI to establish a TDI-induced asthma model. LY294002, a specific inhibitor of PI3K, was given intratracheally 1h before each challenge. Here we showed that airway hypersensitivity, airway infiltration of neutrophils and eosinophils, serum IgE and IL-4 in supernatant of cervical lymphocytes in TDI induced asthmatic mice were all markedly decreased by LY294002, accompanied by suppressed pulmonary expression of HMGB1. At the same time, we observed elevated protein levels of cleaved caspase-1 and IL-1β after TDI challenge, as well as increased immunoreactivity in lung, all of which were significantly recovered by LY294002. While both the protein expression and immunodistribution of NLRP3 in the lung stayed unchanged. These data suggest that PI3K mediates lung caspase-1 activation and HMGB1 production in TDI-induced murine asthma model.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Junjie
J
Liang
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Haijin
H
Zhao
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Lihong
L
Yao
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Haixiong
H
Tang
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Hangming
H
Dong
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Yue
Y
Wu
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Laiyu
L
Liu
School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China.
Fei
F
Zou
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: caishaox@fimmu.com.
Shaoxi
S
Cai
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000378:metabolism; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D014051:Toluene 2,4-Diisocyanate
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014051:Toluene 2,4-Diisocyanate; D058539:Phosphatidylinositol 3-Kinase; D020170:Caspase 1
Asthma; Caspase-1; HMGB1; PI3K; Toluene-diisocyanate