The Therapeutic Drug Screening On Perfluoroisobutylene Inhalation-induced Acute Lung Injury

The mechanism of acute lung injury induced by PFIB inhalation is still unclear, however, plenty of related studies suggested that Ang Ⅱ may be involved in the activation process of the early inflammatory response post PFIB inhalation and MMP activity in damaged lung tissue significantly raised. The above may be used as potential targets for drug design. To attenuate severe lung injury from the process of inflammation activation and blood barrier structure damage, this paper has observed the therapeutic effect of ATI inhibitors and MMP inhibitors on PFIB inhalation-induced acute lung injury. Based on the following hypotheses, i.e. "Ang Ⅱ may be used as a pro-inflammatory cytokines involved in the NF-κB activation and early inflammatory reaction and inhibiting Ang Ⅱ may improve ALI", and "In latent period, inhibition of MMP activity released from PMN can attenuate blood barrier injury and improve symptoms of ALI", we carried out the following experiments:1. The therapeutic effect of ARB on PFIB inhalation-induced ALI1.1 The therapeutic effect of losartan potassium on PFIB inhalation-induced ALIThrough observation of lung wet to dry rate, BALF total protein content at 24 h post PFIB exposure, PFIB inhalation-induced acute lung injury has the following characteristics:1) There is a certain latent period before ALI; 2) lung coefficient, total protein content in BALF and the lung pathology damage are not synchronized. Then, taking AT1 specific inhibitor-losartan potassium as the tool drug, lung coefficients and total protein content in BALF at 24 h post PFIB exposure were detected to evaluate the degree of lung tissue damage at different administraten time and drug dose conditions. The result showed that it just slightly attenuated the ALI, to treat with losartan potassium at 1 h before and 1 h post PFIB exposure and the therapeutic effect of losartan potassium on PFIB inhalation-induced acute lung injury had no significant time-effect relationship. Dose-response relationship experiments showed that there was no difference between different losartan potassium doses:from 1.25 to 15 mg/kg. With reference to the previous research about NF-κB activation (significantly increased trend withinl-3 h post PFIB exposure) and the change of Ang II and ACE/ACE2 content, we hypothesized that Ang Ⅱ may not be involved in PFIB-induced inflammatory reaction.1.2 The therapeutic effects of ARB on PFIB inhalation-induced ALIZD7155 is the latest ATI specific inhibitor and its AT1 selectivity is 100 times more than losartan potassium. To prove the hypothesis that the poor therapeutic effect of losartan potassium on PFIB inhalation-induced ALI attributed to its low AT1 inhibition rate, we detected the change of lung coefficients, total protein content in BALF of and the survival rate within 72 h post PFIB exposure and compared the therapeutic effects of ZD7155 (20 mg/kg) and losartan potassium (40 mg/kg) which were administrated by intraperitoneal injection at 0.5 h before or 0.5,1 h post PFIB exposure. The results showed that, losartan potassium and ZD7155 can decrease lung coefficients and protein content in BALF and the latter appeared to be more effective than losartan potassium, despite absence of statistical difference. Based on the above results, we concluded that the hypothesis of low AT1 inhibition rate-induced poor treatment effect was not real and Inhibition of AT1 was not sufficient to inhibit the early inflammatory reaction and there was no significant therapeutic effect by blocking AT1 on acute lung injury induced by PFIB inhalation.2. The therapeutic effect of MMP inhibitors on PFIB inhalation-induced ALIThe research group screened No.803 from many MMP inhibitors, which had a significantly preventive effect on PFIB inhalation-induced ALI.To estimate the therapeutic effect and the marketing potential of No.803, the experiments took ilomastat as a positive control, which is the latest broad-spectrum MMP inhibitor designed by glycomed company. Lung coefficients, the contents of total protein and phospholipid in BALF, MMP-2,9 and NE activity were detected to compare the therapeutic effects of ilomastat and No.803. It turned out that No.803 seem to be more effective than ilomastat at the decreasing lung coefficients and total protein content in BALF at 24 h post PFIB exposure. However, the results of gelatin zymography analysis suggested that MMP-2,9 activity were not significantly suppressed, which was not with the original intention to inhibit MMP. The reason of the above phenomena might be interpreted by the inappropriate administraten MMP inhibitors or the wrong type of pharmaceutical preparaten.3. ConclusionWe had attempted to attenuate PFIB inhalation-induced ALI by taking the inflammatory response and blood barrier damage as the intervention targets. It suggested that Ang II receptor blockers might not be of importance for prerventing and treating PFIB-induced ALI. However, the candidate chemical of No.803, as a MMP inhibitor, showed significant therapeutic effects on PFIB-induced ALI and suggested a good prospect for development.