| Perfluoroisobutylene (PFIB) is produced as a main by-product in tens of thousands of ton quantities in the fluoropolymer industry. As a highly toxic compound, a brief inhalation of PFIB can result in acute lung injury, pulmonary edema and even death. No specific antidote or successful therapeutic measures are currently available.The phenomena what Lehnert et al observed by electron microscope is that the accumulation of blood monocytes and polymorphonuclear neutrophils (PMNs) in the lung's capillary bed was one of the early responses to PFIB inhalation, but unfortunately they didn't clarify the exact significance of this interesting phenomena in the whole pathologic process of PFIB induced acute lung injury (ALI). Wang et al in our group not only confirmed this phenomenon through the time-course study of myeloperoxidase (MPO) activity in the lungs of mice after PFIB inhalation, but also revealed that PMNs play a vital role in the pathogenesis of PFIB induced ALI in that the mortality and the extent of lung injury of the mice were dramatically alleviated when the mice were depleted of PMN by pretreatment of the animals with cyclophosphamide before PFIB exposure. Polymorphonuclear leukocyte (PMNs) play a vital role in the pathogenesis of the disease, but the underlying mechanism of PMN sequestration in the lung and following acute lung injury induced by PFIB inhalation remained to be further clarified.In order to address the two above questions, the roles of NF-kB activation, on the one hand, were initiated and investigated by evaluating the inhibitory effects of pyrrolidinedithiocarbamate (PDTC), an NF-kB activation inhibitor, on the activation of NF-kB, the expression of cytokines (IL-1B and IL-8) as well as the extent of lung injury after PFIB exposure. On the other hand, the roles of neutrophil elastase (NE) activation were initiated and investigated by evaluating the inhibitory effects of tetracycline hydrochloride (TET), an NE activation inhibitor, as well as the extent of lung injury after PFIB exposure. The main results are summarized as follows:1. The research of PMN sequestration mechanism in the lung and drug intervention.1.1. The NF-kB activity in lungs and effects of PDTC on ALI induced by PFIB inhalationActivation of NF-kB in lungs of mice was determined by Electrophoresis mobility shift assay (EMSA) at 0.5, 1, 2, 4 and 8 h after PFIB inhalation. Increased activation of NF-kB in lungs was observed at 0.5 h and maintained till 1 h with abrupt recovery to the baseline at 2,4 and 8 h after PFIB inhalation, respectively. PDTC pretreatment (120 mg/kg, 30 min before PFIB challenge) could significantly decrease NF-kB activation at 0.5 h after PFIB inhalation.1.2. The levels of cytokines in sera and effects of PDTC in ALI induced by PFIB inhalationThe level of IL-1B in sera dramatically increased at 0.5 h and reached its maximum at 1 h, after which the values quickly returned to the baseline at 2 h post PFIB exposure. The PDTC pretreatment (as above mentioned) could reduce serum IL-1B significantly at 1 h post PFIB exposure, after which no differences were observed compared with that of the PFIB group.The time course of levels of IL-8 in sera of PFIB-exposed mice exhibited different changing tendency with that of IL-1B, with a highlight at 1 h and followed by a plateau till 4h post PFIB challenge. Similarly to the changes of serum IL-1B, the PDTC pretreatment could inhibit the increase in serum IL-8 level significantly at 1 h post PFIB exposure, after which no differences were observed compared with that of thePFIB group.1.3. Effects of PDTC on ALI induced by PFIB inhalation in miceCharacteristics of the effects of PDTC administration at different time-points onPFIB inhalation induced ALLThe values representing the extent of lung injury were all determined at 24 h post PFIB exposure. It was observed that pretreatment with PDTC (120mg/kg, 30 min before PFIB exposure) could significantly lower the wet/dry lung-to-body weight ratio, the water content in the lung an... |
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