Diisodecyl Phthalate Exacerbated Allergic Asthma Through Aggravating Oxidative Stress And The Activation Of P38 MAPK

Diisodecyl phthalate(DIDP)is a environmental plasticizer because of its good physical and chemical properties and weak toxicity.It should be used in all aspects of production and life.The interaction of DIDP as plasticizer and polymer macromolecule is unstable and migrate into food,water,or air.It enters the body through diet,breathing and skin contact,and brings potential harm to human health.Epidemiology has found that the metabolites of DIDP in human urine are closely related to asthma.However,the effect of DIDP exposure on asthma is not clear,and its mechanism is not known.In allergic asthma,oxidative damage caused by reactive oxygen species(ROS),which causes airway hyper-responsiveness(AHR)and inflammation,is considered to be an important mechanism.Studies have shown that p38 MAPK pathway plays an important role in inflammation and airway remodeling.In this study,we set up an asthma mouse model with ovalbumin(OVA)sensitization and stimulation to explore the effect of DIDP exposure on asthma mice.By antagonizing oxidative damage and blocking the p38 MAPK pathway,we explored respectively the potential molecular mechanisms of the possible oxidative stress and the activation of p38 MAPK to promote asthma by DIDP exposure.In this study,specific pathogen free(SPF)male Balb/c mice were randomly divided into 11 groups:Saline group(Saline),DIDP(15 mg/kg/day),ovalbumin(OVA)group,DIDP(0.15,1.5,15,150 mg/kg/day)+ OVA group,DIDP(15 mg/kg/day)+ OVA +blockers group(DIDP 15 + OVA + Vitamin E;DIDP 15+OVA+SB203 5 80),OVA +blockers group(OVA + Vitamin E;OVA + SB203580).According to experimental grouping and experimental process,saline or OVA was intraperitoneal injection on days 7 and 14 respectively.Saline,DIDP or Vitamin E(30 mg/kg/day)were given by intragastric gavage from day 0-20.DIDP 15 + OVA + SB203580 and OVA + SB203580 group of mice were intraperitoneal injection 1 hour before OVA sensitization on days 21,23,26.The dose of SB203580 is 5 mg/kg/day.From day 21-27,the mice were subjected to an aerosol of 1%OVA or saline(30 min/day).The effect of DIDP on mice with allergic asthma was explored by detecting pathological changes in the lung,airway hyper-responsiveness,and total immunoglobulin-E(T-IgE)changes in the serum;The level of ROS,glutathione(GSH)and malondialdehyde(MDA)were measured to evaluate the oxidative damage caused by DIDP exposure;detection of Thymic stromal lymphopoietin(TSLP)in lung tissue,interleukin-4(IL-4),interleukin-13(IL-13),interleukin-1β(IL-1β),interleukin-17A(IL-17A),and γ-interference(IFN-γ)in lung tissue or bronchoalveolar lavage fluid(BALF)to evaluate Th2 and Th17 immune responses induced by DIDP exposure;by detecting the changes of pathological tissue,AHR,oxidative damage level and expression of inflammatory cytokines after antagonism of Vitamin E,we investigated the potential molecular mechanisms by which DIDP exposure may involve oxidative stress mechanism;by examining the phosphorylation levels of p38 MAPK and Th17 immune responses after blockade with SB203580,we investigated the potential molecular mechanisms by which DIDP exposure may involve the activation of p3 8 MAPK and promote asthma.The results of the experiment showed that the exposure to 15 mg/kg DIDP alone in mice significantly increased asthma-like symptoms.Compared with OVA group,airway remodeling was increased in DIDP(0.15,1.5,15,150)+ OVA group,airway hyper-responsiveness(AHR)was enhanced,the expression of T-IgE,TSLP and other cytokines increased,and as the DIDP exposure concentration increased,these asthma-like symptoms were significantly enhanced.Under the sensitization and challenge of OVA,DIDP exposure promoted the secretion of Th2 cytokines such as IL-4 and IL-13,while the expression of IFN-y decreased.At the same time,DIDP exposure also increased the expression of Th17 cytokine IL-17A and phosphorylation of p38 MAPK was enhanced.Examination of ROS,MDA,and GSH showed that DIDP exposure promoted oxidative damage.The antagonism of oxidative damage by Vitamin E and blockade of p38 MAPK pathway through SB203580 significantly reduced asthma-like symptoms in DIDP exposed and OVA-sensitized animals.The manifestations were as follows:airway remodeling was reduced,airway hyper-responsiveness(AHR)weakened,T-IgE,TSLP,ROS,MDA,IL-4,IL-13,IL-1β,IL-17A expression downregulated,p38 MAPK phosphorylation level decreased,and there was a significant difference.In conclusion,exposure to DIDP promoted asthma like lesions in sensitized mice.DIDP exposure not only enhanced Th2 immune response,but also promoted Thl7 immune response.It also reveals that DIDP exposure is a molecular mechanism to promote asthma through oxidative stress and p3 8 MAPK activation.These findings will provide a scientific basis for the clinical treatment of allergic asthma and expand our understanding of the adverse effects and potential mechanisms of DIDP exposure to allergic asthma.