ABSTRACT
Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Subject(s)
Animals , Colitis , Inflammatory Bowel Diseases/drug therapy , Phosphodiesterase 4 InhibitorsABSTRACT
Establishing a suitable animal model is important for studying the mechanism of inflammatory bowel disease (IBD) and exploring new therapeutic approaches. Although a large number of IBD single gene knockout animal models have been established, single knockout of certain genes associated with human IBD susceptibility does not manifest symptoms of IBD or manifest extremely milder symptoms, while composite animal models based on other modeling factors can better simulate the clinical features of IBD. This article mainly introduces three novel composite animal models and elaborates the possible pathogenesis of each composite model:animal models established by gene double knockout have more obvious and earlier symptoms than single-knockout models; single gene knockout model with Helicobacter infection can help to study the role of microbial infections in the pathogenesis of IBD; on the basis of gene knockout, specific deletion of certain immune cells can be used to study the role of the immune cells in the development of IBD. Among the above composite animal models, double knockout mice may be important animal models for IBD study.
Subject(s)
Animals , Humans , Disease Models, Animal , Gene Knockout Techniques , Inflammatory Bowel Diseases , Genetics , Allergy and Immunology , Mice, Knockout , ResearchABSTRACT
Aim To explore the effect of adenylate cyclase(AC) antagonists SQ22536 and agonist forskolin on acute lung injury induced by lipopolysaccharide.Methods ICR mice were randomly divided into normal saline control group(N group), model group(group L), dexamethasone group(group D),AC antagonists s(group SQ) and AC agonist group(group F).The ALI mouse model was induced by instilling intratracheally with LPS(2 mg·kg-1), and 6 h later, the lung tissue and alveolar lavage fluid(BALF) were harvested, pathological changes in lung were observed, white blood cell and neutrophil, albumin content in BALF and myeloperoxidase(MPO) activity of lung tissue homogenate were determined, and tumor necrosis factor α(TNF-α), interleukin-1β(IL-1β), interleukin 6(IL-6) and cAMP content in lung homogenates were detected by ELISA.Results Compared with normal saline group, a large number of neutrophils infiltrated around the pulmonary vessel and airway 6 h after LPS intratracheal instillation in model group.White blood cells and neutrophils and protein content increased in BALF;MPO activity and cAMP levels increased in lung tissues.In the lung tissue TNF-α and IL-6, IL-1β content increased, compared with model group.Forskolin could improve the pathological changes of lung tissue, reduce the total number of leukocytes, number of neutrophils and protein content in BALF, and reduce MPO activity and TNF-α content in lung tissue, at the same time it increased the cAMP content;SQ22536 had no significant effect when compared with model group.Conclusion AC agonists have protective effects on LPS-induced acute lung injury in mice, and the mechanism may be related to elevating cAMP levels, inhibiting neutrophil adhesion and chemotaxis and reducing inflammatory factor levels.
ABSTRACT
Aim Toestablishanexcellentratasthmamodel from using OVA+pertussis sensitized, OVA sensitized and per-tussissensitizedrats.Methods Thethreemethodswereusedto sensitize rats;methacholine bronchial provocation tests were per-formed to determine airway hyperresponsiveness;bronchoalveolar lavage fluid ( BALF) was prepared after the animals were chal-lenged by nebulized antigen. The differential white cell count in BALF was performed, and lung tissue was detected by morpho-logicalanalysis.Results AllofOVA+pertussissensitization,OVA sensitization and pertussis sensitization could deteriorate lung function, increase inflammatory cells and cause pathological change, and OVA + pertussis sensitized rat model had better effect than OVA sensitized and pertussis sensitized rat models. Conclusion OVA+pertussissensitizationandOVAaerosolisa successful rat asthma model.
ABSTRACT
Phosphothesterases [PDE] hydrolyse intracellular cAMP and cGMP to inactive 5' monophosphates Decreased level of cAMP is involved in the pathogenesis of asthma. We and others have shown that phosphodiesterases were upregulated in the lung of allergic rats, and Bacilli Calmette-Guerin [BCG] induced the production of cAMP in vitro. However, it is unclear how BCG's effect asthma and whether it is related to PDEs. In this study, BCG was intraperitoneally injected into male Sprague-Dawley rats sensitrized and later the rats were challenged with ovabumin/pertusis. The inflammation in lungs was measured. Airway hyperresponsiveness was determined using MedLab software after intravenous methacholine challenge. Furthermore cAMP level and adenylate cyclase activity in lungs were analyzed by ELISA, Phosphodiesterases activities were analyzed by HPLC, while PDEs mRNA levels in lungs was analyzed by reverse transcription-polymerase chain reaction. Administration of BCG significantly attenuated allergen-induced lung inflammatory response and hyper responsiveness as compared with vehicle treatment. Furthermore, the levels of cAMP in lungs were significantly increased in BCG-treated allergic rats. Interestingly, administration of BCG decreased the activity of cAMP-PDE, but not adenylyl cyclase [AC], activity in lungs of animals. Furthermore, pretreatment with BCG significantly decreased the mRNA levels of PDE4A, 4C, 5 and 8, which were induced in lungs of allergic rats. BCG administration attenuated airway inflammatory response and bronchial hyper responsiveness in rats, which are the most important symptoms in asthma. The decreased PDEs mRNA and inhibited cAMP-PDE activities by BCG contribute, at least in part, prevention of allergen-induced airway inflammation and asthma in rats