Effects of mindfulness in patients with mild cognitive impairment with insomnia: A double-blind randomized controlled trial.

OBJECTIVE: Current research on the effects of mindfulness therapy on MCI and insomnia has been inconsistent. It is still a hot topic of research and discussion. This study aimed to improve the sleep quality, cognition, and mental state of patients with mild cognitive impairment (MCI) with insomnia. METHODS: A double-blind randomized controlled trial was conducted. Seventy-five patients who met the eligibility criteria were randomly assigned to the mindfulness (n = 38) or health education (n = 37) treatment group. The primary outcomes were sleep, measured by the Pittsburgh Sleep Quality Inventory, and cognition, measured by The Montreal Cognitive Assessment and Mini-Mental State Examination. Secondary outcomes included insomnia, measured by the Insomnia Severity Index, depression, anxiety, and perceived stress. EEG signals were collected at rest with eyes closed in the mindfulness state. The power spectrum was analyzed from these data. RESULTS: Cognitive function and sleep quality were significantly improved in the mindfulness group (95% confidence interval 0.04 - 0.05, 0.03 - 0.04, -5.58 - -1.55, respectively). Anxiety and perceived stress scores were significantly lower than those in the control group (95% confidence interval 0.002 - 0.004, 0.009 - 0.013, respectively). The power spectrum differences in δ, θ, ß, and γ bands were significant between the rest and mindfulness states (P < .05). Good safety was achieved in both groups with no deaths or serious adverse events. CONCLUSION: Mindfulness improved sleep quality, cognitive function, and mentality of patients. Mindfulness practice caused deep relaxation in the brain and changes in electrical frequency bands associated with attention and cognitive tasks. Mindfulness learning can be performed successfully for individuals with MCI. Additionally, it is suitable for adoption in nursing homes.

Effects of expressive arts therapy in older adults with mild cognitive impairment: A pilot study.

Expressive arts therapy (EAT) can potentially improve cognition and mental health in patients with dementia. However, limited studies have been conducted for older adults with mild cognitive impairment (MCI). The aim of this study was to examine the effects of EAT in older adults with MCI. A total of 48 participants with MCI were assigned to the EAT intervention (n = 24) or waiting list control (n = 24) group. The former received 60-90 min of EAT twice a week for 6 weeks. The findings showed that the EAT program had a high retention and attendance rate and a high level of general satisfaction. Moreover, the intervention group showed significant improvements in general cognitive function, language function, anxiety, depression, and the psychological and social relationship domains of quality of life. The results provide preliminary evidence for the feasibility and efficacy of EAT intervention in older adults with MCI.

Effects of Creative Expressive Arts-based Storytelling (CrEAS) programme on older adults with mild cognitive impairment: protocol for a randomised, controlled three-arm trial.

INTRODUCTION: Early non-pharmacological interventions can prevent cognitive decline in older adults with mild cognitive impairment (MCI). Creative expression (CrExp) can potentially mitigate cognitive decline and enhance the physical and mental health of older people. However, it is unclear whether activities involving CrExp can improve cognitive function and other health-related outcomes in older adults with MCI. The aim of the present study is to develop a Creative Expressive Arts-based Storytelling (CrEAS) programme that integrates verbal and non-verbal expressive activities and evaluate its effectiveness in improving cognitive function and other outcome indicators so as to explore its possible mechanism from the perspective of neuroimaging. METHODS AND ANALYSIS: This parallel randomised controlled trial with three arms (one intervention and two control arms) will be conducted over a 24-week period. A total of 111 participants will be enrolled and randomised to the CrEAS, recreation and usual activity groups. The CrEAS programme combines visual arts therapy and storytelling (TimeSlips) under the Expressive Therapy Continuum theoretical framework and provides an opportunity for people with MCI to actively engage in activities to improve cognitive function through verbal and nonverbal CrExp. Global cognitive function, specific domains of cognition (memory, executive function, language and attention) and other health-related outcomes (anxiety, depression and quality of life) will be measured at baseline, at the end of the intervention, and at the 24-week follow-up. Structural/functional brain MRI data will be collected at baseline and immediately after the intervention. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Fujian Provincial Hospital (K2018-03-061). The study results will be disseminated through peer-reviewed journals and at academic conferences. TRIAL REGISTRATION NUMBER: ChiCTR1900021526.

Methanol extract of semen Ziziphi Spinosae attenuates ethanol withdrawal anxiety by improving neuropeptide signaling in the central amygdala.

BACKGROUND: Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways. METHODS: Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays. RESULTS: MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS. CONCLUSIONS: These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.

Yinchenhao Decoction Ameliorates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis in Rats by Regulating Phase II Metabolic Enzymes and Transporters.

Yinchenhao Decoction (YCHD), a famous traditional Chinese formula, has been used for treating cholestasis for 1000s of years. The cholagogic effect of YCHD has been widely reported, but its pharmacodynamic material and underlying therapeutic mechanism remain unclear. By using ultra-high-performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry, 11 original active components and eight phase II metabolites were detected in rats after oral administration of YCHD, including three new phase II metabolites. And it indicated that phase II metabolism was one of the major metabolic pathway for most active components in YCHD, which was similar to the metabolism process of bilirubin. It arouses our curiosity that whether the metabolism process of YCHD has any relationship with its cholagogic effects. So, a new method for simultaneous quantitation of eight active components and four phase II metabolites of rhein, emodin, genipin, and capillarisin has been developed and applied for their pharmacokinetic study in both normal and alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis rats. The results indicated the pharmacokinetic behaviors of most components of YCHD were inhibited, which was hypothesized to be related to different levels of metabolic enzymes and transporters in rat liver. So dynamic changes of intrahepatic enzyme expression in cholestasis and YCHD treated rats have been monitored by an UHPLC-tandem mass spectrometry method. The results showed expression levels of UDP-glucuronosyltransferase 1-1 (UGT1A1), organic anion-transporting polypeptide 1A4 (OATP1A4), multidrug resistance-associated protein 2 (MRP2), multidrug resistance protein 1, sodium-dependent taurocholate cotransporter, and organic anion-transporting polypeptide 1A2 were significantly inhibited in cholestasis rats, which would account for reducing the drug absorption and the metabolic process of YCHD in cholestatic rats. A high dose (12 g/kg) of YCHD remarkably increased the expression of UGT1A1, bile salt export pump, MRP2, OATP1A4 in cholestasis rats presented it exhibited the greatest ameliorative effect on cholestasis, also particularly in histopathological examination and reducing levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, and total bile acid. Considering the metabolic process of bilirubin in vivo, the choleretic effect of YCHD is proven to be related to its regulatory action on expression of metabolic enzymes and transporters in cholestatic liver.

Higher risk of myocardial injury in chest pain patients with elevated red blood cell distribution width.

BACKGROUND: High level of red blood cell distribution width (RDW) has been associated with adverse outcomes in coronary artery disease patients. We aimed to investigate the relationship between RDW and the risk of myocardial injury in chest pain patients. METHODS AND RESULTS: We retrospectively reviewed 2078 chest pain patients with suspected acute myocardial infarction. Myocardial injury was defined as high-sensitivity cardiac troponin T (hs-cTnT) >14 ng/L. RDW was associated with hs-cTnT (r = 0.607) and the risk of myocardial injury stepwise increased across increasing RDW quartiles in all subgroups based on age and sex. The receiver operating characteristic curve analysis was calculated to assess the elevated RDW to predict myocardial injury, with the cutoff value of 13.25%. RDW had a high sensitivity (78.10%), specificity (87.44%), as well as positive predictive value (77.48%). The area under the curve (AUC) for all patients was 0.88 (95%CI 0.87, 0.90) and there is no statistical significant in AUCs for all subgroups. CONCLUSIONS: Elevated RDW was significantly associated with a higher risk of myocardial injury in chest pain patients with potential acute myocardial infarction. The RDW may be helpful to identify myocardial injury in such patients.

Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors.

A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 µM) and 10e (IC50 = 0.19 µM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

Standardized transbronchial needle aspiration procedure for intrathoracic lymph node staging of non-small cell lung cancer.

BACKGROUND: Thoracic lymph node (LN) metastasis is the determining factor for NSCLC staging. However, enlargement in thoracic LNs, which can be detected by chest computed tomography (CT), may not be adequate for NSCLC staging. This study aimed to investigate the effectiveness of a new transbronchial needle aspiration (TBNA) procedure to improve the sensitivity and accuracy of lung cancer diagnosis and staging. METHODS: A standardized TBNA procedure was performed on enlarged and non-enlarged LNs in the order of N3 to N1 station according to Wang's LN map. The status of LN metastasis determined by the standardized TBNA procedure was compared with the results from CT scan. RESULTS: The TBNA biopsy revealed that 21.43% of non-enlarged LNs were malignant. Compared with chest CT, the standardized TBNA procedure improved the accuracy of LN metastasis staging and discovered skip LN metastasis. CONCLUSIONS: The standardized TBNA procedure of this study may be recommended to be used as a routine TBNA procedure, in which LNs should be biopsied in the order of N3 to N1 station and both enlarged and non-enlarged LNs should be included to improve the accuracy of lung cancer staging.

[Study on hydrolysis of baicalin into baicalein by immobilized beta-glucosidase in a two-phase system].

The optimum conditions of baicalin hydrolysis into baicalein by immobilized beta-glucosidase in a two-phase system was studied and the yield was observed. A two-phase system comprising of sodium acetate buffer and chloroform was determined by comparing the solubleness of baicalein in different solvents and partition coefficient of baicalein in related aqueous-organic two-phase system. beta-Glucosidase was immobilized by the crosslinking-embedding method using sodium alginate as the carrier The optimum reaction temperature, pH value, Michaelis constant, the thermal stability and pH stability were assayed. By comparing the yield of baicalin hydrolysis into baicalein by immobilized beta-glucosidase in two-phase system, the optimum reaction conditions were determined-the optimum reaction temperature, pH value and time were 50 degrees C, 5.0 and 10 h, respectively. The yield of baicalein was 85.28%. Compare with one-phase system, two-phase system had an advantage in reaction rate and yield.

Simultaneous determination of dihydromyricetin and resveratrol in Ampelopsis sinica (Miq.) W.T. Wang by high-performance liquid chromatography coupled with a diode array detection method.

Yeputaoteng is the dried ground part of Ampelopsis sinica (Miq.) W.T. Wang, which is widely used in traditional Chinese medicine for preventing and treating tumors, chronic nephritis, hepatitis, rubella, traumatic bleeding, stomach heat and vomiting. A simple and reliable method using high-performance liquid chromatography with diode array detection (HPLC-DAD) was developed for the simultaneous determination of dihydromyricetin and resveratrol in Yeputaoteng. The chromatographic analysis was performed on a Dikma C18 column (250 × 4.6 mm, 5 µm) at 30°C with a gradient elution of acetonitrile and 0.1% phosphoric acid at a flow rate of 1 mL/min, and used ultraviolet detection at 292 and 306 nm. The established method was validated in terms of linearity, precision, reproducibility, stability and recovery. The calibration curves showed good linear regression (R(2) > 0.9994). Limits of detection and quantification fell in the ranges of 1.47-2.48 and 2.93-4.97 µg/mL, respectively. The mean recovery of dihydromyricetin and resveratrol was 104.1% [relative standard deviation (RSD): 2.94%] and 100.8% (RSD: 2.80%), respectively. The quantitative results indicated that the HPLC-DAD method can be effectively applied to the quality control of Yeputaoteng and its preparations.

Quantification of conjugated metabolites of drugs in biological matrices after the hydrolysis with ß-glucuronidase and sufatase: a review of bio-analytical methods.

Glucuronidation and sulfation represent two major pathways in phase II drug metabolism in humans and other mammalian species. The great majority of drugs, for example, polyphenols, flavonoids and anthraquinones, could be transformed into sulfated and glucuronidated conjugates simultaneously and extensively in vivo. The pharmacological activities of drug conjugations are normally decreased compared with those of their free forms. However, some drug conjugates may either bear biological activities themselves or serve as excellent sources of biologically active compounds. As the bioactivities of drugs are thought to be relevant to the kinetics of their conjugates, it is essential to study the pharmacokinetic behaviors of the conjugates in more detail. Unfortunately, the free forms of drugs cannot be detected directly in most cases if their glucuronides and sulfates are the predominant forms in biological samples. Nevertheless, an initial enzymatic hydrolysis step using ß-glucuronidase and/or sulfatase is usually performed to convert the glucuronidated and/or sulfated conjugates to their free forms prior to the extraction, purification and other subsequent analysis steps in the literature. This review provides fundamental information on drug metabolism pathways, the bio-analytical strategies for the quantification of various drug conjugates, and the applications of the analytical methods to pharmacokinetic studies.

Metabolism of Genipin in Rat and Identification of Metabolites by Using Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Tandem Mass Spectrometry.

The in vivo and in vitro metabolism of genipin was systematically investigated in the present study. Urine, plasma, feces, and bile were collected from rats after oral administration of genipin at a dose of 50 mg/kg body weight. A rapid and sensitive method using ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF MS) was developed for analysis of metabolic profile of genipin in rat biological samples (urine, plasma, feces, and bile). A total of ten metabolites were detected and identified by comparing their fragmentation patterns with that of genipin using MetaboLynx software tools. On the basis of the chromatographic peak area, the sulfated and glucuronidated conjugates of genipin were identified as major metabolites. And the existence of major metabolites G1 and G2 was confirmed by the in vitro enzymatic study further. Then, metabolite G1 was isolated from rat bile by semipreparative HPLC. Its structure was unambiguously identified as genipin-1-o-glucuronic acid by comparison of its UV, IR, ESI-MS, (1)H-NMR, and (13)C-NMR spectra with conference. In general, genipin was a very active compound that would transform immediately, and the parent form of genipin could not be observed in rats biological samples. The biotransformation pathways of genipin involved demethylated, ring-opened, cysteine-conjugated, hydroformylated, glucuronidated, and sulfated transformations.

[Study on the extraction process and macroporous resin for purification of Timosaponin B II].

OBJECTIVE: To optimize the extraction process and macroporous resin for purification of Timosaponin B II from Anemarrhena asphodeloides. METHODS: Orthogonal design L9 (34) was employed to optimize the circumfluence extraction conditions by taking the extraction yield of Timosaponin B II as index. The absorption-desorption characteristics of eight kinds of macroporous resins were evaluated, then the best resin was chosen to optimize the purification process conditions. RESULTS: The optimum extraction conditions were as follows: the herb was extracted for 2 times (2 hours each time) with 8.5-fold 50% ethanol at the first time and 6-fold 50% ethanol at the second time. HPD100 resin showed a good property for the absorption-desorption of Timosaponin B II. The optimum technological conditions of HPD100 resin were as follows:the solution concentration was 0.23 mg/mL, the amount of saturated adsorption at 4/5 body volumn (BV) resin, the HPD100 resin was washed with 3 BV water and 6 BV 20% ethanol solution to remove the impurity, then the Timosaponin B II was desorbed by 5 BV ethanol solution. The purity of Timosaponin B II was about 50%. CONCLUSION: The optimized extraction process and purification is stable, efficient and suitable for industrial production.

[Research on the preparative method of Arctigenin].

OBJECTIVE: To research on the preparation of Arctigenin in vitro. METHODS: Took enzyme concentration, time course and substrate concentration as investigation factors, used Box-Behnken design-response surface methodology to optimize the enzyme hydrolysis path of Arctigenin. RESULTS: The best operational path for Arctigenin was as follows: the temperature was 50 degrees C, pH was 4.8, enzyme concentration was 0.44 U/mL, time course was 46.81 min, substrate concentration was 0.29 mg/mL, the conversion rate was 90.94%. CONCLUSION: This research can be regarded as a referencein preparing Arctigenin in vitro.

Effects of krill oil on serum lipids of hyperlipidemic rats and human SW480 cells.

BACKGROUND: Cardiovascular disease (CVD) and colon cancer incidence are known to be closely related to dietary factors. This article evaluated effects of krill oil (KO) on serum lipids of hyperlipidemia rats and human colon cancer cells (SW480). Serum lipids of rats fed with high fat diet (HFD) and different doses of KO were measured by automatic analyzer. Effect of KO on viability of cells was determined by methyl thiazolyl tetrazolium (MTT) assay. RESULTS: Except for higher dose group, body weights decreased significantly. Total cholesterol (TC), LDL-cholesterol (LDL-C) of all dose groups, Triglycerides (TG) of low and mid dose groups descended significantly, while there were no significant differences of HDL-cholesterol (HDL-C), compared with control group. Treatment of colon cancer cells with KO also resulted in time-dependent inhibition of cell growth. CONCLUSION: Our findings indicated that the consumption of KO may provide benefits to control serum lipid levels in certain diseases and inhibit growth of colon cancer cells. Therefore, KO may be a good candidate for development as a functional food and nutraceutical.

[Effects of Fuzheng Huayu recipe on MMP-2 activity and type IV collagen expression at fibrotic lung].

OBJECTIVE: To study the mechanism of Fuzheng Huayu (FZHY) recipe against pulmonary fibrosis relating to MMP-2 activity and type IV collagen expression at lung tissue. METHOD: The pulmonary fibrosis model was induced by intratracheal instillation with bleomycin once in rats. The models were divided into 3 groups: model control, FZHY recipe treated, and methylprednisolone (Solu-Medrol) treated group, each group was of 14 model rats. Normal control group with 10 rats was intoxicated with the same amount of saline. From the second day of intoxication, FZHY recipe treated group orally took FZHY recipe at the dosage of 4.6 g x kg(-1) rat wt, methylprednisolone treated group received intraperitoneal injection with 15 mg x kg(-1) rat wt of methylprednisolone, while model and normal controls took the same volume of saline, 1 time each day and lasting for 4 weeks. Lung and body weights were weighed and the lung/body ratio was calculated. Collagens deposition was check with Masson stain, and lung hydroxyproline (Hyp) content was assayed with Jamall's method. Protein expressions of MMP-2/9 and type IV collagen at lung tissue were analyzed with Western blot and of MMP-2/9 activities by gelatin zymography. RESULT: Compared to normal rats, the model control rats had a high lung/body ratio, remarkable collagen deposition, increased Hyp content and the expressions of type IV collagen, MMP-2 and MMP-9 protein at lung tissue, increased MMP-2 activity, in particular active MMP-2 activity, but decreased MMP-9 activity. Compared to model control, FZHY recipe and methylprednisolone obviously attenuated pulmonary collagen deposition, decreased lung/body ratio and Hyp content, downregulated MMP-2 protein expression and activity, in particular active MMP-2 activity, and FZHU recipe had some better actions than methylprednisolone on lung/body ratio, type IV collagen expression and active MMP-2 activity. But both drug groups had no influence on MMP-9 protein expression and activity. CONCLUSION: FZHY recipe has a good action against experimental pulmonary fibrosis and its mechanisms are associated with the inhibition of MMP-2 protein and activity, and with the inhibition of over expression of type IV collagen at lung tissue.

[Feature changes of MMP-2/9 activities and TIMP-1/2 protein expressions during the progression of pulmonary fibrosis in rats].

OBJECTIVE: To investigate the dynamic trends of activities of matrix metalloproteinase (MMP)-2/9 and protein expressions of their inhibitors-tissue inhibitor of matrix metalloproteinase (TIMP)-1/2 during the progression of pulmonary fibrosis in rats so as to get insight of the roles played by MMP-2/9 in lung injury and fibrogenesis. METHODS: Forty-eight SD rats were randomly divided into normal control group (n=18) and bleomycin (BLM)-treated group (n=30). The pulmonary fibrosis was induced by intratracheal injection of BLM once. At the consecutive time of 1 day, 3 days, 1 week, 2, 3, and 4 weeks after intoxication, the lung-to-body weight ratio was calculated and the inflammation and collagen deposition in lung tissue were checked by HE and Masson stainings respectively. Meanwhile, the content of hypdroxyproline (Hyp) in lung tissue was assayed with Jamall's method, the protein expressions of MMP-2/9, TIMP-1/2 were examined by Western blotting, and the activities of MMP-2/9 were detected by gelatin zymography. RESULTS: The histopathological changes in lung tissue in the BLM-treated group from 1 day to 2 weeks after intoxication presented local lesions, broadened alveolar wall and septum, infiltration with lots of inflammatory cells and few of fibroblasts inside alveolar space and septum. At this early stage in the BLM-treated group, the lung-to-body weight ratio was increased significantly, the protein expressions and activities of MMP-2/9 were obviously increased especially for activity of active MMP-2, and the protein expressions of TIMP-1/2 were also increased gradually, as compared with those in the normal control group. From 3 to 4 weeks after intoxication in the BLM-treated group, the alveolar structure was damaged, parts of the alveolar space collapsed and replaced by collagens and fibroblasts, and the alveolar wall and septum obviously widened with remarkable fibrotic characteristics, as compared with those in the normal control group. Meanwhile, the lung-to-body weight ratio and the activities of MMP-2/9 were decreased in the BLM-treated group as compared with those in the same group at 2 weeks after intoxication, but the content of Hyp and the protein expressions of TIMP-1/2 were both increased dramatically, especially at 4 weeks after intoxication. CONCLUSIONS: During the lung fibrogenesis induced by BLM in rats, the alveolar inflammation is the most important alteration with enhanced MMP-2/9 activities in the early stage. While in the late stage, the main change is displayed as pulmonary fibrosis, characterized by increased TIMP-1/2 and declined MMP-2/9 activities.