| Paraquat(PQ), has been widely used as a contact herbicide throughout the world. Along with the widespread use of paraquat in our country, PQ poisoning is becoming a more and more serious clinical problem. PQ is readily absorbed through skin, pneogaster or enter0n. It is highly toxic to human beings and other animals. The human lethal oral dose is on the order of 30 to 40mg/kg. But the poisoning mechanism has not been fully elucidated, and there are no known pharmacological antagonists for paraquat heretofore. A high mortality rate is encountered in poisoning cases, it is reported that the mortality rate can exceed 80% in clinical practice. The lung is the most susceptible target organ, which also determines the major reason of death. Serious PQ poisoning generally causes acute respiratory failure induced by acute pulmonary injury and multiple organ dysfunction syndrome (MODS). Whereas the light PQ poisoning leads to a little longer course of disease as compared with the serious poisoning, frequently gives rise to late pulmonary fibrosis primarily and causes death finally by respiratory failure.In the earlier stage, PQ poisoning mainly induces an acute alveolitis, and then brings about a progressive pulmonary interstitial fibrosis. The exact mechanism of pulmonary toxicity of PQ has not been fully elucidated. As alveolitis is the major appearance of PQ poisoning in its earlier course, in which many kinds of proinflammatory cytokines involve, p38, a member of family of mitogen activated protein knases (MAPK), as the substrate of many kinds of inflammatory stimulation, regulates the pathophysiological procedure of inflammatory diseases through its signaling pathway, and mediates the procedures of cell stress responses, immune responses, and cell growth, development, division, programmed cell death and coordination of cell functions, etc. While the nuclear factor kappa B (NF-κB), plays a key role in modulating the inflammatory reaction of the network of inflammatory cytokines as the omnipresent transcriptional factor of eukaryocyte. Importantly, some researches recently found that NF-κB could be activated by free radicals, and inhibited by antioxidants. Recent researches showed extracellular matrix (ECM) deposition diffusely leads to pulmonary fibrosis, especially the imbalance of the synthesis and degradation of ECM contributes to the development of pulmonary fibrosis. Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinnases (TIMPs) play important roles in the process of the synthesis and degradation of ECM, and in the domain of promotor of some MMPs genes exists the binding sites of NF-κB. Transforming growth factor-131 (TGF-β1) is the most important cytokine among them, it can promote fibroblast to synthesize extracellular matrix such as collagen protein, fibronectin, proteoglycan, etc, and to facilitate the precipitation of ECM. It can also reduce the degradation of extracellular matrix and increase the generation of prolease inhibitor, and so as to play an important role in the procedure of pulmonary fibrosis.Melatonin (MT) is the indoleamine hormone secreted from pineal body. Some reports indicated that MT not only is high effective in eliminating free radicals directly, but also is easy to diffuse through cell membrane, cytoplasm and nucleus with its high lipophilicity, so as to eliminate the free radicals and to inhibit the increase of peroxide-lipid in different tissues. Its another important function is to increase the activity of antioxidase, thus it is able to effectively protect the microbiomolecules such as lipid, DNA from the free radical damage. As the most powerful endogenous radical scavenger known at present, it is speculated that MT may play a noticeable role in relieving peroxidation damage and inhibiting the development of pulmonary fibrosis.The changes of p38MAPK, NF-κB, TGF-β1, MMPs, and TIMPs in the process of PQ-induced pulmonary injury and the effect of MT have not been reported in the domestic and international. In this study, we observed the expressions of p38MAPK, NF-κB, TGF-β1, MMPs, TIMPs, and the pathological changes in pulmonary tissues in different time points with or without the treatment of MT, so as to elucidate the possible mechanism and the therapeutic effect of Melatonin on lung injury induced by PQ poisoning. The experiments contained three parts as below:Part 1: The Pulmonary Interstitial Changes Induced by Paraquat and Its Regulating MechanismsObjectives: To observe serum malonyldialdehyde (MDA) concentration, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activity and the expressions of MMPs, TIMP-1 in the rat model of paraquat-induced pulmonary injury.Methods: Forty-eight adult healthy Sprague-Dawley (SD) rats were randomly divided into two groups: (1) Control group (group A): 6 rats; (2) Poisoned group (group B): 42 rats. Group B were treated intragastrically with 1ml of PQ (50mg/kg) diluted with normal saline. Group A were treated with the same dose of normal saline as in group B. Six rats were taken blood samples from heart through thoracotomy with ketamine anaesthesia in day 1, day 3, day 7, day 14, day 21, day 28 and day 35, respectively. Serum SOD, GSH-Px activity and MDA concentration were measured at the corresponding time points. The expressions of MMP-2, MMP-9, and TIMP-1 rnRNA in the lung homogenate were measured by reverse transcription-polymerase chain reaction (RT-PCR) and hydroxyproline (HYP) levels in homogenate were also measured. Pathology of lung tissues was observed by HE staining and Masson staining. The expressions of MMP-2, MMP-9, and TIMP-1 in lung tissues were detected by immunohistochemistry (IH) staining. The other part of the lung was stained to observe the ultra-structure by using electron microscope. Rats in group A received the same treatment as in group B.Results: 1. Intoxication manifestations Intoxication manifestations occurred in rats only 0.5-2 hours after PQ, and were especially severe during the first three days. Intoxication involves a combination of signs and symptoms including lethargy, hypoxia, dyspnea, tachycardia, hyperpnea, ataxia, hyperexcitability, convulsions, unhairing, nose and/or eyes bleeding, diarrhea and marked losses in body weight. Intoxication manifestations were relieved gradually after the first 3 days and the body weight increased after the 7th day,2 Serum and homogenate measurement:â‘ The levels of MDA in group B were significantly higher than that in group A on the 1st, 3rd and 7th day (P<0.01), and returned to the similar level of group A after the 14th day (P>0.05).â‘¡The activity of serum SOD in group B significantly decreased on the 1st day, and remained lower compared with group A on the 7th day (P<0.05); and returned to the similar level of group A after the 14th day (P>0.05).â‘¢The activity of GSH-Px in group B was significantly lower than that in group A on the 1st, 3rd day (P<0.05); and returned to the similar level of group A after the 7th day (P>0.05).â‘£There were no significant differences between group A and group B in HYP contents of homogenate of lung tissues on the 1st, 3rd, 7th day (P>0.05), but the contents of HYP in group B were significantly higher than that in group A after the 14th day (P<0.05).3 Histological changes:â‘ HE staining: Group A: The normal alveolar wall was thin and clear, with no infiltration of inflammatory cells in the lumen of alveoluses or occasionally only a few erythrocytes. Group B: At the earlier stage, there were obvious changes of acute alveolitis from day 1 to day 3, such as pulmonary edema, diffuse pulmonary hemorrhage, the infiltration of inflammatory cells and hyaline membrane; At the later stage, we also observed proliferation of collagen fibers, fibrous thickening of the alveolar wall and fibroblastial hyperplasia in different degrees.â‘¡Masson staining: In group A, Only a bit of stained green collagen fibres were found in the areas around bronchia and the interspace between alveoluses, whereas in group B, after the 14th day, fibrous thickening occurred in bronchia walls and the alveolus interspacea, in some areas with an irregular collocation of collagen fibres, with a higher percentage of positive area than that of group A (P<0.05).â‘¢Electron microscope: No obvious abnormal changes were found in ultrastructure of lung tissues in group A. In group B, inflammatory transudate containing fractured organelles, erythrocytes were found in the alveolus cavity, with obvious basilemma rupture and damage of alveolar typeâ… cells; following that is the alveolus intervals thickening, which containing abundant proliferated hypertrophic alveolar typeâ…¡cells and vacuolizated lamellar body as well as the growth of collagenfibre under the alveolar epithelia and toward to capillary basilemma.4 Immunohistochemistry (IH) staining:â‘ In group A, there was only a very weak expression of MMP-2, MMP-9 and TIMP-1 in bronchial epithelial cells, alveolar epithelial cells and pulmonary macrophages.â‘¡The expressions of MMP-2, MMP-9 and TIMP-1 in group B were significantly higher than that in group A on the 1st day (P<0.01), which were observed in bronchial epithelial cells, alveolar epithelial cells, pulmonary macrophages, vascular endothelial cells and some other interstitial cells, the expression of MMP-2 returned to the similar level of group A on the 35th day (P>0.05), and the expression of MMP-9 returned to the similar level of group A on the 21th day (P>0.05), but the expression of TIMP-1 still remained higher than that in group A till day 35 (P<0.01).5 MMP-2, MMP-9 and TIMP-1 mRNA:â‘ There was only a very weak expression of MMP-2, MMP-9, and TIMP-1 mRNA in group A.â‘¡MMP-2 mRNA: In group B, there was a significant higher level of expression of MMP-2 mRNA on the 1st day, which reached the peak on the 7th day, and decreased afterwards but still remained significantly higher than that in group A on the 28th day (P<0.05), and returned to the similar level of group A on the 35th day (P>0.05). MMP-9 mRNA: In group B, the expression of MMP-9 mRNA increased on the 1st day (P<0.01), peaked on the 3rd day, and remained higher than that in group A on the 7th day (P<0.01), and got to the level of group A after the 14th day (P>0.05). TIMP-1 mRNA: The expression of TIMP-1 mRNA increased significantly on the 1st day (P<0.01), peaked on the 14th day and continued at the high level till day 35 (P<0.01).Conclusions: 1. The characteristic changes of PQ-induced lung injury were acute pulmonary alveolitis initially with subsequent pulmonary fibrosis.2. Oxidative insult and the imbalance of oxidation-antioxidation system were the main mechanisms of PQ-induced lung injury.3. The dynamic changes of MMP-2, MMP-9, and TIMP-1 in PQ-induced lung injury leaded to the imbalance of the synthesis and degradation of ECM, and contributed to the development of pulmonary fibrosis.Part 2: The Changes of NF-κB, TGF-β1, and Phosphorylated p38MAPK in PQ-Induced Lung InjuryObjectives: To study the role of p38MAPK, NF-κB activation and TGF-β1 in PQ-induced lung injury.Methods: Forty-eight adult healthy Sprague-Dawley (SD) rats were randomly divided into two groups. (1) Control group (group A): 6 rats; (2) Poisoned group (group B): 42 rats. Six rats were taken blood samples from heart through thoracotomy with ketamine anaesthesia in day 1, day 3, day 7, day 14, day 21, day 28 and day 35, respectively. The activity of NF-κB was assayed with electrophoretic mobility shift assay (EMSA), Western blot method was used to detect the expression of the phosphorylated p38MAPK, the expressions of MMP-2, MMP-9, TIMP-1, and TGF-β1 rnRNA inthe lung homogenate were measured by RT-PCR, and the expressions of MMP-2, MMP-9, TIMP-1, TGF-β1, and NF-κBp65 protein were measured by immunohistochemistry staining. Rats in group A received the same treatment as in group B.Results: 1. Immunohistoehemistry (IH) staining:â‘ In group A, there was only a very weak expression of MMP-2, MMP-9, and TIMP-1 in bronchial epithelial cells, alveolar epithelial cells and pulmonary macrophages (P<0.01). The expressions of MMP-2, MMP-9 and TIMP-1 in group B were significantly higher than that in group A on the 1st day (P<0.01), which were observed in bronchial epithelial cells, alveolar epithelial cells, pulmonary macrophages, vascular endothelial cells and some other interstitial cells, the expression of MMP-2 returned to the similar level of group A on the 35th day (P>0.05), and the expression of MMP-9 returned to the similar level of group A on the 21th day (P>0.05), but the expression of TIMP-1 still remained higher than that in group A on the 35th day (P<0.01).â‘¡In group A, there was only a very weak expression of NF-κBp65 in bronchial epithelial cells and mainly in cytoplasma. In group B, the positive area of NF-κBp65 remarkably increased, and were observed in cytoplasma and nucleus of bronchial epithelial cells, alveolar epithelial cells, pulmonary macrophages, vascular endothelial cell and other interstitial cells. The percentage of positive area of NF-κBp65 was remarkably higher than that in group A from day 1 to day 14 (P<0.01), and returned to the similar level of group A on the 21st day (P>0.05).â‘¢In group A, there was only a very weak expression of TGF-β1 in bronchial epithelial cells, a few vascular endothelial cells and occasionally in alveolar macrophages. In group B, the expression of TGF-β1 was significantly higher than that in group A on the 1st day (P<0.01). In the earlier stage, the expression was mainly located in bronchial epithelial cells, a few alveolar epithelial cells and vascular endothelial cells, and then the expression was mainly located in alveolar macrophages and some other interstitial cells, and remained significantly higher compared with group A on the 35th day (P<0.01).2. MMP-2, MMP-9, TIMP-1 and TGF-β1mRNA:â‘ There was only a very weak expression ofMMP-2,MMP-9, TIMP-1, and TGF-β1 mRNA in group A.â‘¡In group B, there was a significant higher level of expression of MMP-2 mRNA on the 1st day, which reached the peak on the 7th day, reduced afterwards but still remained significantly higher than that in group A on the 28th day (P<0.05), and got to the similar level of group A on the 35th day (P>0.05). The expression of MMP-9 mRNA increased on the 1st day (P<0.01), peaked on the 3rd day, and remained higher than that in group A on the 7th day (P<0.01), and got to the level of group A after the 14th day (P>0.05). The expression of TIMP-1 mRNA increased significantly on the 1st day (P<0.01), peaked on the 14th day and continued at a high level, and still remained significantly higher than that in group A even on the 35th day (P<0.01). The expression of TGF-β1 mRNA increased significantly on the 1st day, peaked on the 14th day, and continued at a high level till day 35 (P<0.01).3. NF-κB activity: There was only very low activity of NF-κB in normal lung homogenates in group A. The activity of NF-κB in group B increased markedly on the 1st day (P<0.01), peaked on the 3rd day (P<0.01), and remained higher from day 7 to day 14 (P<0.01), and returned to the similar levels of group A after the 21th day (P>0.05).4. Phosphorylated p38MAPK protein expression: Only a weak expression of phosphrylated p38MAPK was found in group A, while in group B, the expression of phosphorylated p38MAPK increased markedly on the 1st day (P<0.01), peaked on the 3rd day (P<0.01), remained higher from day 7 to day 14 (P<0.05), and returned to the similar level of group A after the 21th day (P>0.05).Conclusions: In the present research, we found that PQ poisoning significantly increased the expressions of NF-κB, p38MAPK and TGF-β1, which correlated closely with the abnormal expressions of MMPs/TIMPs. The complicated interactions among them were involved with the procedures of inflammatory pulmonary injury, damage of tissue structure as well as the following tissue repair, which contributed to the development of pulmonary injury and pulmonary fibrosis. Among them, the significantly higher expressions of NF-κB and p38MAPK in the earlier stage indicated that NF-κB and p38MAPK might play the important roles in the development of alveolitis, while TGF-β1 might be the key factor to induce pulmonary fibrosis as it still sustained at the significantly higher level in the later stage.Part 3: The Molecular Mechanisms of Melatonin in Treating Acute Lung Injury Induced by PQ Poisoning.Objectives: To assess the protective effects of Melatonin on PQ poisoning through observing the dynamic changes of serum MDA, SOD, GSH-Px and the expressions of MMPs, TIMPs, NF-κB, TGF-β1, and p38MAPK in pulmonary tissues of PQ poisoning rats model.Methods: Ninety adult healthy Sprague-Dawley (SD) rats were divided into three groups at random. (1) Control group (group A): 6 rats, (2) Poisoned group (group B): 42 rats, and (3) Melatonin group (group C): 42 rats. Group B and group C were treated intragastrically with lml of PQ (50mg/kg) diluted with normal saline. Group A rats were treated with the same dose of normal saline as group B and group C. Additionally, Group C rats were given Melatonin at a dose of 10mg/kg diluted with normal saline (once daily, intraperitoneally) immediately after the administration of the PQ. Group A and group B were treated with the same dose of normal saline (once. daily, intraperitoneally) as group C. Six rats were taken blood samples from heart through thoracotomy with ketamine anaesthesia in day 1, day 3, day 7, day 14, day 21, day 28, and day 35 after paraquat treatment, respectively. Serum levels of SOD, GSH-Px activity and MDA concentration were measured; and hydroxyproline (HYP) levels in homogenate were also measured; The expressions of MMP-2, MMP-9, TIMP-1, and TGF-β1 mRNA in lung homogenate were measured by RT-PCR; The activity of NF-kB was assayed with EMSA; Western blot method was used to detect the expressions of the phosphorylated p38MAPK protein; and Samples from lung tissues were oberserved by HE staining, Masson staining and immunohistochemistry (IH) staining. Rats in group A received the same treatment as group B and group C.Results: 1. Intoxication manifestations Rats in group B manifested as lethargy, hypoxia, dyspnea, tachycardia, hyperpnea, ataxia, hyperexcitability, convulsions, unhairing, nose and/or eyes bleeding, diarrhea and marked body weight loss. As compared with that in Group B, rats in Group C demonstrated the alleviated symptom and behaviors, especially in dyspnea and loss of weight.2. Serum and homogenate measurement:â‘ The serum levels of MDA in group B were significantly higher than those in group A on the 1st, 3rd, 7th day(P＜0.01), whereas the increases of serum levels of MDA were markedly inhibited in group C, the levels of serum MDA were significantly lower compared with group B on the 1st, 3rd, 7th day (P＜0.05). Compared with those in group A, the statistically significant higher levels of MDA in group C only kept on the 1st, 3rd day (P＜0.05).â‘¡The serum levels of SOD in group B were significantly lower than those in group A on the 1st, 3rd, 7th day (P＜0.05); MT treatment significantly increases the levels of SOD activity in group C and remained higher than those in group B on the 1st, 3rd, 7th day (P＜0.05). Compared with those in group A, the statistically lower levels of SOD in group C only kept on the 1st, 3rd day (P＜0.05).â‘¢The activity of GSH-Px in group B was significantly lower than that in group A on the 1st, 3rd day (P＜0.05), while the activity of GSH-Px in group C was remarkably increased, and was higher than that in group B on the 1st, 3rd day (P＜0.01), and similar to that in Group A all over the period (P＜0.01).â‘£There were no significant differences between group A and group B in HYP contents in homogenate of lung tissues on the 1st, 3rd, 7th day (P＞0.05), but the contents of HYP in group B were significantly higher than those in group A after the 14th day (P＜0.05); There were no significant differences between group A and group C in HYP content in lung homogenate on the 1st, 3rd, 7th ,14th day (P＞0.05), but the contents of HYP in group C were significantly higher than those in group A after the 21th day, but markedly lower compared with that in group B (P＜0.05).3. Histological changes:â‘ HE staining: Group A: The normal alveolar wall was thin and clear, without soakage of inflammatory cells in the lumen of alveoluses, or occasionally only a few erythrocytes. Group B: At the earlier stage, there were obvious changes of acute alveolitis, such as pulmonary edema, diffuse pulmonary hemorrhage, inflammatory cell infiltration and hyaline membrane formation. At the later stage, proliferation of collagen fibers, fibrous thickening of the alveolar wall and fibroblastial hyperplasia in different degrees were commonly observed. In group C, MT significantly alleviated the acute alveolitis in those rats with PQ poisoning, which exhibited a degree just between the group A and group B in the earlier stage, and a noticeable inhibition on the proliferation of collagen fibres even in the later stage.â‘¡Masson staining: In group A, only a bit of stained green collagen fibres were found in the areas around bronchia and the interval between alveoluses, while in group B, after the 14th day, fibrous thickening occurred in bronchia walls and the alveolus intervals, in some areas with an irregularcollocation of collagen fibres, with a higher percentage of positive area than that in group A (P＜0.01). In group C, the proliferation of the stained collagen fibers were not seen from day 1 to day 14, and increased gradually after the 21st day, but markedly lower than that in group B (P＜0.05).4. Immunohistochemistry (IH) staining:â‘ There was only a very weak expression of MMP-2 in group A. while in group B, there was already a significant higher expression of MMP-2 from day 1 to day 28 after PQ poisoning (P＜0.05), and returned to the similar level of group A onthe 35th day (P＞0.05). the expression of MMP-2 in group C was significant lower than that in group B from day 1 to day 28 (P＜0.05), though still statistically higher than that in group A from day 1 to day 21 (P＜0.01).â‘¡The expression of MMP-9 was very weak in group A, while a significant higher expression of MMP-9 was already found in group B compared with group A from day 1 to day 14 after PQ poisoning (P＜0.05). In contrast, the expression of MMP-9 in group C was significant lower than that in group B from day 1 to day 14 (P＜0.01), though it was markedly higher than that in group A from day 1 to day 7 (P＜0.05).â‘¢The expression of TIMP-1 was very weak in group A, while a significant higher expression of TIMP-1 was already found in group B compared with group A from day 1 to day 35 (P＜0.01). In contrast, the expression of TIMP-1 in group C was significantly lower than that in group B along with the whole time points (P＜0.01), though it was markedly higher than that in group A all over the period (P＜0.01).â‘£There was only a very weak expression of NF-kBp65 in group A, while it kept in a sustained significant higher level in group B compared with group A from day 1 to day 14 after PQ poisoning (P＜0.01), In contrast, the expression of NF-kBp65 in group C was significantly lower than that in group B from day 1 to day 14 (P＜0.01), though it was still obvious higher than that in group A from day 1 to day 7 (P＜0.01).⑤There was only a very weak expression of TGF-β1 in group A, while it kept in a sustained significant higher level in group B compared with group A from day 1 to day 35 (P＜0.01), In contrast, the expression of TGF-β1 in group C was significantly lower than that in group B along with the whole time points (P＜0.01), though it was also obvious higher than that in group A all over the period (P＜0.01). 5. MMP-2, MMP-9, TIMP-1, and TGF-β1 mRNA:â‘ MMP-2 mRNA: A small quantity of MMP-2 mRNA were measured in normal lung tissues, while there was already a significant higher expression of MMP-2 mRNA even on the 1st day after PQ poisoning in group B (P＜0.01), which reached the peak on the 7th day, remained significantly higher than that in group A from day 14 to day 28 (P＜0.05), and got to the similar level of group A on the 35th day (P＞0.05). The expression of MMP-2 mRNA in group C was significant lower than that in group B from day 1 to day 28 (P＜0.05), but remained higher than that in group A from day 1 to day 14 (P＜0.01), and reached the similar level of group A on the 21th day (P＞0.05).â‘¡MMP-9 mRNA: The expression of MMP-9 mRNA was very weak in normal pulmonary tissues in group A, while a significant higher expression of MMP-9 mRNA was already found in group B on the 1st day after PQ poisoning (P＜0.01), which reached the peak on the 3rd day and then decreased gradually along with the time process and returned to the similar level of group A on the 14th day (P＞0.05). The expression of MMP-9 mRNA in group C was significant lower than that in group B from day 1 to day 7 (P＜0.05), which kept the higher level only on the 1st day and 3rd day, and reached to the similar level of group A on the 7th day (P＞0.05).â‘¢TIMP-1 mRNA: There was only a very weak expression of TIMP-1 mRNA in normal pulmonary tissues in group A, while a significant higher expression of TIMP-1 mRNA was already found in group B even on the 1st day after PQ poisoning (P＜0.05), which reached the peak on the 14th day and kept at the higher level till day 35 (P＜0.01). The expression of TIMP-1 mRNA in group C was significant lower than that in group B along with the whole time points (P＜0.05), although it was still markedly higher than that in group A from day 1 to day 28 (P＜0.05).â‘£TGF-β1mRNA: Only a very weak expression of TGF-β1 mRNA was found in normal pulmonary tissue in group A, the expression of TGF-β1 mRNA in group B increased significantly on the 1st day (P＜0.01), peaked on the 14th day (P＜0.01), and continued at a high level till day 35 (P＜0.01). The expression of TGF-β1 mRNA in group C was significant lower than that in group B along with the whole time points (P＜0.05), though it was also obvious higher than that in group A all over the period (P＜0.05).6. NF-kB activity: There was only very low activity of NF-kB in normal lung homogenates in group A. The activity of NF-kB in group B increased markedly on the 1st day (P＜0.01), peaked on the 3rd day, and remained significantly higher than that in group A from day 7 to day 14 (P＜0.01). The activity of NF-kB significantly decreased in group C all the time points compared with group B (P＜0.01), which reached the peak on the 1st day, gradually decreased and returned to the similar level of group A on the 14th day (P＞0.05).7. Phosphorylated p38MAPK protein expression: Only a weak expression of phosphrylated p38 was found in group A. However, in group B, the expression of phosphorylated p38MAPK markedly increased on the 1st day (P＜0.01), peaked on the 3rd day, and then decreased gradually along the time process and reached the similar level of group A on the 21st day (P＞0.05). The expression of phosphorylated p38MAPK in group C was significant lower than that in group. B from day 1 to day 14 (P＜0.01), but remained higher than that in group A from day 1 to day 7 (P＜0.05), and returned to the similar level of group A on the 14th day (P＞0.05).Conclusions: MT treatment significantly decreased the levels of serum MDA, increased the activity of SOD and GSH-Px in PQ poisoning rats. Meanwhile, MT treatment markedly alleviated the pulmonary inflammatory process in the earlier stage, prevented evidently from the tendency of pulmonary fibrosis in the later stage. The underlying mechanism might due to its powerful antioxidant property, the role of MT in regulating the balance between MMPs and TIMPs, decreasing the expression of TGF-β1, phosphorylated p38MAPK, as well as decreasing the activity of NF-rB in pulmonary tissue.
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