Humans ; Paraquat ; poisoning ; Pulmonary Fibrosis ; chemically induced ; pathology

Adult ; Antitubercular Agents ; adverse effects ; Humans ; Isoniazid ; adverse effects ; Male ; Pulmonary Fibrosis ; chemically induced ; diagnosis

BACKGROUNDBleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.

METHODSBleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days. We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.

RESULTSSimvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (I and III) mRNA expression induced by bleomycin. Moreover, simvastatin down-regulated the increased expression of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-alpha (TNF-alpha) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore, the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.

CONCLUSIONSSimvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-beta1 and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.

Animals ; Antibiotics, Antineoplastic ; Bleomycin ; Mice ; Mice, Inbred C57BL ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; Simvastatin ; pharmacology

OBJECTIVETo evaluate the effect of water channel aquaporin 4 (AQP4) on bleomycin-induced lung fibrosis in mice.

METHODSIn wild type and AQP4 gene knockout (AQP4-/-) mice, lung fibrosis was induced by injection of bleomycin (3 mg/kg) into the trachea and saline injection was used as a control. At d3, 7, 14, 28 after bleomycin-treatment, mice were randomly sacrificed in batch and the lung coefficient was determined. Serum levels of TGF-β1 and TNF-α were measured by ELISA and hydroxyproline contents in lung tissue were determined by Alkaline hydrolysis method. H-E staining and Masson's staining were performed to examine the pathological changes of lung tissues after bleomycin-treatment.

RESULTSOn d14 after bleomycin-treatment, the lung coefficients in wild type mice and AQP4-/- mice were 1.9-fold (12.69 ± 6.05 vs 6.80 ± 0.82, q=4.204, P<0.05) and 2.3-fold (14.05 ± 5.82 vs 6.05± 0.58, q=5.172, P<0.01) of that in control, respectively, but no significant difference was found between wild type and AQP4-/- mice in the lung coefficient value (P>0.05). The hydroxyproline contents in the lung increased after bleomycin-treatment; on d28, the lung hydroxyproline contents in wild type and in AQP4-/- mice were 1.55-fold (0.85 ± 0.22 g/mg vs 0.55 ± 0.14 μg/mg, q=4.313, P<0.05) and 1.4-fold (0.84 ± 0.13 μg/mg vs 0.60 ± 0.14μg/mg, q=4.595，P<0.05) of that in control, respectively, but no significant difference was noticed between wild type and AQP4-/- mice in lung hydroxyproline contents. There was a tendency that serum TGF-β1 and TNF-α levels increased in bleomycin-treated mice, but no significant difference was found between wild type and AQP4-/- mice. AQP4-knockout showed no effects on pathological changes of lung tissues with H-E staining and Masson's staining in mice with bleomycin-induced lung fibrosis.

CONCLUSIONAQP4 might not be involved in bleomycin-induced lung fibrosis in mice.

Animals ; Aquaporin 4 ; genetics ; Bleomycin ; toxicity ; Male ; Mice ; Mice, Knockout ; Pulmonary Fibrosis ; chemically induced ; genetics

OBJECTIVETo observe the lung injury in rats induced by SiO₂ nanoparticles.

METHODSOne hundred and fifty SD rats were divided into five groups: the control group, the nanosized SiO₂ groups of 6.25, 12.5, 25 mg/ml, and the microsized SiO₂ group of 25 mg/ml, 30 rats each group. On the 7th, 15th, 30th, 60th and 90th day after exposure, six rats were sacrificed at each time point and the lung viscera coefficient, the pathological morphology and ultrastructure of lung were observed.

RESULTSAt each time point, the rat lung viscera coefficient of 25 mg/ml microsized SiO₂ and nanosized SiO₂ group were higher than the physiological saline group (P < 0.05), 25 mg/ml microsized SiO₂ group was higher than the same dose of nanosized SiO₂ group (P < 0.05); With longer duration of dye dust, lung viscera coefficient of 25 mg/ml microsized SiO₂ group and each dose of nanosized SiO₂ group were in time-effect relationship. Under light microscope we can see microsized SiO₂ group gradually formed cellularity nodules, and fused into fibrous nodules; At the early stage 25 mg/ml nanosized SiO₂ group occured focal alveolar macrophages and fibroblast proliferation and later fibrous connective tissue proliferated. Under TEM osmium lamellar corpuscle of type II alveolar epithelial cells were abnormal, and collagen and elastic fiber proliferated in mesenchyme of microsized and nanosized SiO₂ group.

CONCLUSIONNanosized SiO₂ particles after exposure can cause lung tissue injury in rat, and at the early stage it is showed inflammation, and later mainly characterized by pulmonary interstitial fibrosis differing from nodular lung fibrosis caused by microsized SiO₂, its ability to fibrosis is weaker compared with the same concentration of microsized SiO₂.

Animals ; Lung ; drug effects ; pathology ; ultrastructure ; Lung Injury ; chemically induced ; Male ; Nanoparticles ; toxicity ; Pulmonary Fibrosis ; chemically induced ; pathology ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity

OBJECTIVETo observe the effects of Fuzheng Huayu Recipe (FHR) on rat's renal interstitial fibrosis induced by mercuric chloride (HgCl2), and to explore preliminarily its mechanism of action.

METHODSRats were randomly divided into four groups: the normal group, the model group, the FHR group and the vitamin E group, the latter two were treated respectively by FHR 4.6 g/kg and vitamin E 100 mg/kg. Rats model was established by oral administration of 8 mg/kg HgCl2 for 9 weeks. Serum creatinine (Cr) and urea nitrogen (BUN) content were tested with corresponding test kits; hydroxyproline (Hyp) content in kidney was assayed with hydrochloric acid hydrolysis; renal histologic change was observed with HE, Masson and methenamine silver (PASM) staining; and collagen type I (Col I), as well as protein expressions of fibronectin (FN) and alpha-smooth muscle actin (alpha-SMA) was determined with Western blot.

RESULTSCompared with the model group, the kidney/body weight ratio, serum levels of Cr and BUN, kidney Hyp content, and severity of renal interstitial fibrosis in the two treated groups were significantly lower (P<0.05 or P<0.01), and the improvements were more significant in the FHR group than those in the vitamin E group; Col I and FN protein expression was also weaker in the two treated group (Col, P<0.05; FN, P<0.01); while the expression of alpha-SMA was lower in the FHR group (P<0.01), but it wasn't in the vitamin E group (P>0.05).

CONCLUSIONFHR could improve the HgCl2-induced renal function injury in rats, decrease extracellular matrix deposition and restrain renal interstitial fibrosis, the mechanism of action might be related with its inhibitory effect on myofibroblast activation.

Animals ; Drugs, Chinese Herbal ; therapeutic use ; Fibrosis ; chemically induced ; Kidney Diseases ; chemically induced ; drug therapy ; pathology ; Male ; Mercuric Chloride ; Phytotherapy ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the pulmonary toxicity to rats induced by the nanosized SiO(2) or the standard SiO(2).

METHODSSeventy-two male SD rats were divided into three groups: the nanosized SiO(2) group, the standard SiO(2) group and the control group. 24 rats each group. The nanosized SiO(2) group and the standard SiO(2) group were instilled intratracheally with 0.5 ml suspension of 0.6 mg/ml nanosized SiO(2) or standard SiO(2) respectively while the control group was instilled with 0.5 ml physiological saline. On the 3rd, 7th, 14th, and 28th day after exposure, six rats were sacrificed at each time point and the total white cells counts and total protein in BALF and the histopathological changes were observed. The pulmonary toxicities of the two SiO(2) dusts were compared.

RESULTSNanosized SiO(2) caused significant increase at 3rd, 7th, 14th day after the exposure [(16.0 +/- 6.0) x 10(6), (11.1 +/- 4.0) x 10(6), (12.2 +/- 4.6) x 10(6)] compared with saline (P < 0.05 or P < 0.01) in the total numbers of white cells and on the 3rd after the exposure compared with standard SiO(2) [(5.7 +/- 3.7) x 10(6), P < 0.01]. Meanwhile, Nanosized SiO(2) significantly increased the total protein on the 14th, 28th day after the exposure (0.41 +/- 0.14, 0.41 +/- 0.19 g/L) compared with saline or standard SiO(2) and nanosized SiO(2) on the 3rd, 7th day after the exposure (P < 0.05 or P < 0.01). Nanosized SiO(2)-treated rats showed marked white cell infiltration in alveolar space or around brondum the blood vessel. Standard SiO(2) caused similar but less severe responses compared with nanosized SiO(2). Van Gieson's-stained sections showed no significant fibrosis in these dust-exposed rats at 28th day after the exposure.

CONCLUSIONNanosized SiO(2) can cause severer and longer pulmonary toxicity in rats than standard SiO(2). The pulmonary particle load threshold of nanosized SiO(2) may be lower than that of standard SiO(2).

Animals ; Male ; Nanoparticles ; toxicity ; Particle Size ; Pulmonary Fibrosis ; chemically induced ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity

Peyronie's disease is characterized by local fibrosis of the tunica albuginea and relatively rare clinically. Few relevant basic researches could be retrieved, which might be attributed to the absence of a robust animal model of the disease as well as to its rareness. At present, some animal models available for Peyronie's disease have their own merits and demerits. TGF-β1-induced and Fibrin-induced models are lack of penile curvature and calcification/ossification. A surgical model might be established for the acute phase of the disease. The characteristic of a widespread fibrotic process involving many organs in the spontaneous model is quite different from that of human Peyronie's disease. Therefore, choosing the right model is essential for researches. This paper presents an overview of the animal models of Peyronie's disease, meant to provide some reference for the basic research of the disease.
Animals ; Disease Models, Animal ; Fibrin ; Fibrosis ; Humans ; Male ; Penile Induration ; chemically induced ; pathology ; Penis ; pathology ; Transforming Growth Factor beta1

Paraquat (PQ) is a highly effective herbicide with contact toxicity. PQ mainly accumulates in the lungs after absorption into the blood circulation. The respiratory function failure caused by PQ-induced lung injury, especially the irreversible pulmonary fibrosis in late phase, is the leading cause of death in patients with PQ poisoning. The mechanism of PQ poisoning is still unclear. Now it is speculated that oxidative stress and inflammation injury are the main pathogenic mechanisms, and abnormal gene expression, mitochondrial damage, loss of pulmonary surfactant, cytokine network and unbalanced matrix metalloproteinases/tissue inhibitors may be also involved in the pathogenesis. In addition to reducing poison absorption and increasing its removal, the current clinical treatment is mainly composed of antioxidant and anti-immune response, but has poor therapeutic effects. Although many novel methods of treatment have been proposed, most of them are still in the experimental stage. It is a hot spot to clarify the mechanism of PQ poisoning and to seek safe and effective treatment of pulmonary fibrosis. This article reviews the research progress on pathogenesis and treatment of PQ-induced pulmonary fibrosis.
Antioxidants ; Gene Expression ; Humans ; Inflammation ; Lung ; pathology ; Oxidative Stress ; Paraquat ; poisoning ; Pulmonary Fibrosis ; chemically induced ; pathology ; therapy

OBJECTIVETo evaluate effect of amygdalin on expression of four biomarkers in the animal model of pulmonary fibrosis induced by bleomycin.

METHODSRats were given one dose (5 mg/kg) of bleomycin in bleomycin-treated groups, amygdalin-treated groups and saline in controls by intratracheal instillation exposed surgically. The amygdalin-treated groups rats were treated with intraperitoneal injection of amygdalin (15 mg x kg(-1) x day(-1)). The rats were sacrificed 7, 14 and 28 days after bleomycin administration. Polarized light microscopy and Image-Pro Plus detected I and III collagen expressed in Paraffin-embedded lung sections stained with Sirius red. Surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS) with weak cationic proteinchip (CM10) detected differentially expressed proteins in the pooled serum samples of all groups.

RESULTSConsistent fibrotic responses were found in all bleomycin and amygdalin-tread groups. On the 7th, 14th and 28th day after bleomycin or saline instillation, four differentially expressed proteins were detected in the pooled serum of all groups rats, consisting of 4 proteins with mass/charge ratio of 3530.7, 7043.5, 8332.6 and 9068.0, respectively. Compared with control groups, protein peaks intensity ratio with mass/charge ratio of 3530.7 on 7, 28 d and 7043.5, 8332.6 and 9068.0 on 7, 14 and 28 d was > 2 in bleomycin-treated groups. Compared with amygdalin-treated groups, protein peaks intensity with mass/charge ratio of 3530.7 at 7, 14, 28 d had no change almost, but protein peaks intensity ratio with mass/charge ratio of 7043.5 at 7 d, 8332.6 on 28 d and 9068.0 on 14 d was > 2 in bleomycin-tread groups. All the four protein peaks intensity had no change almost at other point.

CONCLUSIONAmygdalin may reduce the bleomycin-induced increase of differentially expressed protein peak intensities in rat serum.

Amygdalin ; pharmacology ; Animals ; Biomarkers ; blood ; Bleomycin ; adverse effects ; Blood Proteins ; metabolism ; Male ; Pulmonary Fibrosis ; blood ; chemically induced ; Rats ; Rats, Wistar