| Acute lung injury (ALI) is a mainstay of systemic inflammatory response syndrome(SIRS) at lungs, which is characterized by spread of pulmonary infiltration of inflammatory cells, increased pulmonary capillary vascular permeability succeeded by hypoxemia. At the molecular level, ALI is manifested as the excessive release of a variety of inflammatory mediators and inflammatory factors and the imbalance of pro-inflammatory and anti-inflammatory response. At the cell level, ALI shows the accumulation and infiltration of neutrophils, macrophages and other inflammatory cells. The clinical manifestations of ALI stand for the diffuse injury of alveolar vascular endothelial cell, pulmonary edema, pulmonary atelectasis and other pathological features. In severe cases, ALI can lead to acute respiratory distress syndrome (ARDS) or multiple organ dysfunction syndrome(MODS)Drug intervention plays an important role in the prevention and treatment of ALI or ARDS. The clinical application of traditional anticholine drugs such as Anisodamine medicines have been used in the treatment of ALI/ARDS for many years. However, these drugs is limited using widly because of non-selective on cholinergic receptor subtypes as well as adverse reaction.Penehyclidine hydrochoride (PHC) selectively acts on the M1 and M3 receptor while it has no or less action on the M2 receptors. Recent studies have shown that PHC demonstrated effects on improving microcirculation, reducing capillary wall permeability, and decreasing the release of lysosomal discharge. These effects exert cell protection. PHC may have a therapeutic effect on ALI or ARDS.Therefore, this study was designed to observe the effect of PHC on oxidative stress and tumor necrosis factor-a(TNF-a) through the establishment of rat model of endotoxin-induced ALI, and further to explore the protective mechanism of PHC and dose-effect relationship used in ALI.Materials and Methods:Thirty-two male SD rats weighing 230-280g were randomly divided into 4 groups(n=8 each):control group; group M(received LPS only); group L(LPS+low does PHC); group H(LPS+high does PHC); group L and H received intraperitoneal PHC 0.3mg/kg or lmg/kg 30 min before LPS administration. LPS 5mg/kg was administered intravenously in Group M. L and H. The rats were killed at 6 h after LPS administration. The lungs were removed immediately for determination of W/D lung weight ratio and water content. Level of tumor necrosis factor-a(TNF-a) was analyzed by enzyme-labeled immunosorbent assay (ELISA). Content of myeloperoxidase(MPO),malondialdehyde(MDA), activity of superoxide dismutase (SOD), lactate dehydrogenase (LDH) in lung tissue and blood was detected by spectrophotometer. Morphologic change of lung tissue was observed by light microscope and electron microscope. Results:1. TNF-αlevels in serum and lung tissue of rats Compared with group C, TNF-αlevels in group M, L and H increased significantly (P< 0.05); compared with group M, TNF-αlevels in group L and H decreased significantly (P< 0.05), while there also were significant differences between group L and group H (P< 0.05)2. MPO activities in the lung tissue of rats Compared with group C, MPO activities in group M, L and H increased significantly (P< 0.05); compared with group M, MPO activities in group L and H decreased significantly (P< 0.05), while there also were significant differences between group L and group H (P< 0.05)3. MDA levels in serum and lung tissue of rats Compared with group C, MDA levels in group M, L and H increased significantly (P< 0.05); compared with group M, MDA levels in group L and H decreased significantly (P< 0.05), while there also were significant differences between group L and group H (P< 0.05).4. SOD activities in serum and lung tissue of rats Compared with group C, SOD activities in group M, L and H increased significantly (P< 0.05); compared with group M, SOD activities in group L and H decreased significantly (P< 0.05), while SOD activities in group H were much higher than those in group L (P< 0.05)5. LDH activities in serum of rats Compared with group C, LDH activities in group M, L and H increased significantly (P< 0.05); compared with group M, LDH activities in group L and H decreased significantly (P< 0.05), while LDH activities in group H were much lower than those in group L (P< 0.05)6. W/D lung weight ratio and water content in rats Compared with group C, W/D lung weight ratio and water conten in group M, L and H increased significantly (P< 0.05); compared with group M, W/D lung weight ratio and water conten in group L and H decreased significantly (P< 0.05), while W/D lung weight ratio and water conten in group H were much lower than those in group L (P< 0.05)7. Pathological changes of lung tissue Observetion by light microscope and electron microscope was that the structure of lung tissue was normal in group C, seriously injuryed in group M, slightly injuryed in group L and H; meanwhile, the injury in group H was much lighter than that in group L.Conclusion:1. Pretreatment with PHC can mitigate the inflammatory reaction by reducing content of TNF-a in the lung tissue and(or) serum.2. Pretreatment with PHC can improve the ability of rats against oxdative stress by reducing content of MPO and MDA, decreasing activity of LDH and enhancing activity of SOD in the lung tissue and(or) serum.3. Pretreatment with PHC can mitigate alveolar typeⅡepithelial cell damage.4. The lmg/kg of PHC has more significant protective effect to rats of ALI.
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