ABSTRACT
BACKGROUND: Allergic asthma is characterized by inflammation and airway remodelling. Airway remodelling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodelling. However, the role of calpain in airway smooth muscle remodelling remains unknown. OBJECTIVE: To investigate the role of calpain in asthmatic airway remodelling as well as the underlying mechanism. METHODS: The mouse asthma model was made by ovalbumin sensitization and challenge. Calpain conditional knockout mice were studied in the model. Airway smooth muscle cells (ASMCs) were isolated from smooth muscle bundles in airway of rats. Cytokines IL-4, IL-5, TNF-α, and TGF-ß1, and serum from patients with asthma were selected to treated ASMCs. Collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs were analysed. RESULTS: Inhibition of calpain using calpain knockout mice attenuated airway smooth muscle remodelling in mouse asthma models. Cytokines IL-4, IL-5, TNF-α, and TGF-ß1, and serum from patients with asthma increased collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs, which were blocked by the calpain inhibitor MDL28170. Moreover, MDL28170 reduced cytokine-induced increases in Rictor protein, which is the most important component of mammalian target of rapamycin complex 2 (mTORC2). Blockage of the mTORC2 signal pathway prevented cytokine-induced phosphorylation of Akt, collagen-I synthesis, and cell proliferation of ASMCs and attenuated airway smooth muscle remodelling in mouse asthma models. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that calpain mediates cytokine-induced collagen-I synthesis and proliferation of ASMCs via the mTORC2/Akt signalling pathway, thereby regulating airway smooth muscle remodelling in asthma.
Subject(s)
Airway Remodeling , Asthma/metabolism , Asthma/pathology , Calpain/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Muscle, Smooth/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Airway Remodeling/drug effects , Airway Remodeling/genetics , Animals , Asthma/immunology , Calpain/antagonists & inhibitors , Calpain/genetics , Cell Proliferation , Collagen Type I/biosynthesis , Cytokines/metabolism , Dipeptides/pharmacology , Disease Models, Animal , Mice , Mice, Knockout , Myocytes, Smooth Muscle/metabolism , Phosphorylation , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolismABSTRACT
TIM4, which is expressed on dendritic cells and macrophages, plays an important role in the proliferation of T helper type 2 (Th2) cells. Asthma, as a complex genetic disease, is thought to arise from the development of a Th2-lymphocyte-predominant immune response. To evaluate the effects of the promoter polymorphisms (-1419G>A and -1609G>A) in TIM4 on asthma susceptibility, case-control and family-based association studies were conducted by polymerase chain reaction and restriction fragment length polymorphism. Our results showed that TIM4 -1419G>A polymorphism was associated with asthma susceptibility in our study population (chi(2)= 9.88, P < 0.001, OR = 1.91, 95% CI 1.37-2.64). The -1419A/A and -1419A/G genotypes were observed more common in asthmatic group (6.3%, 41.8%) than in control group (1.7%, 29.3%). No significant difference was found in genotype and allele frequencies of TIM4 -1619G>A polymorphism between asthmatic and control groups. No association between the two SNPs and total serum IgE levels, lung function was observed. In conclusion, the present findings suggest that TIM4 -1419G>A polymorphism might be the genetic factor for the risk of childhood asthma in Chinese Han population.
Subject(s)
Asthma/genetics , Genetic Predisposition to Disease , Membrane Proteins/genetics , Adolescent , Alleles , Asian People/genetics , Asthma/epidemiology , Case-Control Studies , Child , Child, Preschool , China/epidemiology , Female , Gene Frequency , Genotype , Haplotypes/genetics , Humans , Logistic Models , Male , Polymorphism, Single Nucleotide , Promoter Regions, GeneticABSTRACT
To our knowledge there has been no report to date of successful testis replantation after complete traumatic severance of the funiculus within the scrotum. We report a case in which both funiculi were cut completely (one of which was severed 0.8 cm. proximal to the upper pole of the testis, and the other just at the junction of the funiculus and the testis). We successfully rejoined the testis with the funicular stump to the proximal cut end of the right side using a microsurgical technique. The total ischemia period of the replanted testis was 6 hours. The penis was erect 4 days postoperatively and blood testosterone level was within the normal range. At testicular biopsy 120 days postoperatively the germ cells could be seen in various stages of development and the appearance of the Leydig cells was normal.
