Comparative Study Of Non-selective And Selective Histone Deacetylase Inhibitors On Inflammatory Response In Rats With Acute Paraquat Poisoning

Objective: Acute paraquat(PQ)poisoning is one of the most serious illnesses in emergency department.Because of being no specific antidote,PQ poisoning has a high mortality rate.The lung is the main target organ.Both acute respiratory distress syndrome occurred in early stage and interstitial fibrosis occurred in advanced stage can cause respiratory failure and eventually lead to death.The main mechanism of PQ poisoning is to cause direct oxidative damage of tissues and promote the production of reactive oxygen species(ROS)in those tissues.Then ROS continuously stimulates the secretion of various inflammatory mediators by inflammatory cells,induce excessive inflammatory reactions and the concurrency of systemic inflammatory response syndrome(SIRS).An immunosuppressive state with signs of lymphopenia could occur after SIRS,which is known as compensatory anti-inflammatory response syndrome(CARS).Both SIRS and CARS can cause multiple organ dysfunction,which in turn causes death.Histone deacetylase(HDAC)is a key enzyme that maintains histone acetylation.Histone deacetylase(HDAC)is the key enzyme that maintains histone acetylation.HDAC inhibitors(HDACI)inhibit histone deacetylation,continuously expose gene transcription sites on chromosomes,upregulate gene transcription,inhibit inflammatory response and improve cell survival.This study aimed to compare the effects of non-selective and selective HDACI on inflammatory response in rats with acute PQ poisoning.Methods: In this study,24 female Wistar rats were randomly divided into 8 groups and the experimental group was given 100mg/kg PQ by gavage and the control group was given 1ml/100 g normal saline(NS)by gavage.The rats were divided into the following groups in detail:(1)normal saline(NS)gavage +(NS+DMSO)intraperitoneal injection;(2)NS gavage +(VPA+DMSO)intraperitoneal injection;(3)NS gavage +(MC1568+NS)intraperitoneal injection;(4)NS gavage +(Apicidin+NS)intraperitoneal injection;(5)PQ gavage +(NS+DMSO)intraperitoneal injection;(6)PQ gavage+(VPA+DMSO)intraperitoneal injection;(7)PQ gavage +(MC1568+NS)intraperitoneal injection;(8)PQ gavage +(Apicidin+NS)intraperitoneal injection...and 30 minutes later,VPA(nonselective class I and class IIa HDACI),Apicidin(selective class I HDACI)and MC1568 (selective class IIa HDACI)were administered by intraperitoneal injection.After 72 hours,the rats were anesthetized with pentobarbital sodium,and arterial blood is collected from the abdominal.The arterial blood gas analysis,blood routine and blood coagulation were tested to evaluate the respiratory function and systemic inflammatory response.Observed the morphological changes of rat lung.The bronchial lavage fluid(BALF)of left lung was collected.HE staining and wet/dry ratio(W/D)of right lung were done to evaluate the damage degree of lung such as alveolar hemorrhage and edema.TNF-α and IL-10 in BALF and blood serum were detected by ELISA,and the levels of these two cytokines were analyzed to evaluate the inflammatory response of lung and the whole body.Results: All rats that given PQ were exposed to different levels of diet and drinking reduction,brought themselves up,decreased activities,and had shortness of breath.While the rats who were given NS gavage did not have those performance that mentioned above.After 72 hours of PQ gavage,the rats developed respiratory failure,which showed a decrease in arterial oxygen partial pressure,and a rise in carbon dioxide partial pressure.Hemorrhage and hematoma were seen in the lung tissue,and W/D was increased.The alveolar septal thickening,blood cells and inflammatory cell infiltration were observed under the light microscopy.Leukocytes and lymphocytes in serum of the poisoned rats were significantly reduced.VPA can increase the arterial oxygen partial pressure and blood PH value of PQ-poisoned rats,and reduce the partial pressure of carbon dioxide.Also,VPA alleviated the bleeding and hematoma of the lung tissue in those poisoned rats,and reduced the lung W/D.It was seen under the microscope that VPA reduced the alveolar septal thickening and the infiltration of blood cells and inflammatory cells caused by PQ.In addition,VPA can reduce the decrease of leukocytes and lymphocytes in serum of poisoned rats.In contrast,MC1568 and Apicidin did not significantly weaken the immunosuppressive state of PQ poisoning rats.Conclusion: Excessive inflammatory response in rats with acute PQ poisoning may further lead to an immunosuppressive state of CARS.VPA can attenuate the immunosuppressive state of CARS in acute PQ poisoning rats and maintain the immune system in stable trend.In contrast,MC1568 and Apicidin did not significantly weaken the immunosuppressive state of PQ poisoning rats.