The Protective Effect Of Heme Oxygenase-1 And Its Catalytic Product Biliverdin On Seawater Drowning-induced Lung Injury

Heme oxygenase-1(HO-1)is a rate-limiting enzyme of heme degradation which catalyzes the degradation of the prooxidant molecule heme to carbon monoxide(CO)and biliverdin(BV)with cytoprotective properties.A large number of studies have shown that HO-1 has protective effects against acute lung injury(ALI)or acute respiratory distress syndrome(ARDS)caused by various harmful factors.Drowning is one of the most common causes of accidental death worldwide.Seawater drowning usually causes ALI/ARDS with pathological features such as pulmonary hemorrhage,pulmonary edema and hypoxemia.Studies have shown that HO-1 expression is up-regulated in seawater drowning-induced lung injury in mice.However,the role of HO-1 in seawater drowning-induced lung injury and its mechanism are still unclear.The aim of this study was to investigate the mechanism and therapeutic potential of HO-1 in seawater drowning-induced lung injury with experiments in vivo and in vitro.In this study,a seawater drowning-induced lung injury model in mice was established.The lung injury model was verified by gross and pathological morphology of lung tissue,lung wet/dry weight ratio,serum lactate dehydrogenase(LDH)activity,and lung tissue superoxide dismutase(SOD)activity.The lung tissue self-repair was found in the late stage of seawater drowning-induced lung injury.The expression and activity of HO-1 protein in seawater drowning-induced lung injury was detected by Western blot and HO-1 activity assay.The results suggested that the enhanced expression and activity of HO-1 existed during the self-repair process after seawater drowning in mice.The inhibition of HO-1 activity by zinc protoporphyrin(ZnPP)revealed that the inhibition of HO-1 enzyme activity would aggravate the severity of seawater drowning-induced lung injury,inhibit the proliferation of lung tissue cells and promote pulmonary fibrosis and apoptosis of lung cells in mice.In this study,we also established a model of seawater-induced cell damage in A549 cells.The mechanism of seawater-induced cell damage was clarified through cell morphology,CCK-8,LDH activity,expression of inflammatory cytokines and cell proliferation-related factors,apoptosis and oxidative stress injury.The HO-1 inducer Hemin and the HO-1 activity inhibitor ZnPP were used to regulate HO-1 expression and activity levels,in order to explore the role and mechanism of HO-1 in seawater-induced cell damage.The results indicated that HO-1 mitigated seawater-induced cellular inflammatory response,oxidative stress damage and apoptosis through exerting its enzymatic activity.Interfering with cells by using exogenous BV,BV was found to have a protective effect on seawater-induced cell damage.In conclusion,HO-1 could protect against seawater drowning-induced lung injury through its enzymatic activity,and its protective mechanism might relate with anti-inflammatory,anti-oxidation,cell proliferation and inhibition of apoptosis.BV,an enzyme catalytic product of HO-1,might have therapeutic effects,and bring new possibilities for clinical treatment of seawater drowning-induced lung injury.