allopurinol and Pulmonary-Fibrosis

Combined pulmonary fibrosis and emphysema (CPFE) is a relatively new entity within the spectrum of cigarette smoke induced lung disorders. Currently there is no consensus about its treatment. We hypothesized that caveolin-1 critically determines the parenchymal and vascular remodeling leading to the development of CPFE. We assessed the effect of therapeutic targeting of caveolin-1 in mesenchymal and endothelial cells by the phosphodiesterase-5 inhibitor, sildenafil.. Male Wistar rats (n = 168) were exposed to; room air (control); bleomycin (7 U/kg), bleomycin+sildenafil (50 mg/kg/day P.O.), cigarette smoke (CS) (4 Gold Flake 69 mm/day), CS + sildenafil, CS + bleomycin, CS + bleomycin+sildenafil. Animals were euthanized at 8, 9, 11, 12 weeks and lung histopathological changes, collagen deposition, ROS, Xanthine oxidase, caveolin-1 determined.. Cigarette smoke causes progressive ROS accumulation, caveolin-1 up-regulation in alveolar epithelial cells, alveolar macrophages, peribronchiolar fibroblasts, endothelial and vascular smooth muscle cells, interstitial inflammation and emphysema. Sildenafil reduces oxidative stress, parenchymal caveolin-1 and attenuates emphysema caused by CS. Bleomycin increases lung ROS and downregulates caveolin-1 leading to fibroblast proliferation and fibrosis. Combined cigarette smoke and bleomycin exposure, results in differential caveolin-1 expression and heterogeneous parenchymal remodeling with alternating areas of emphysema and fibrosis. Increased caveolin-1 induces premature senescence of lung fibroblasts and emphysema. Decreased caveolin-1 is associated with propagation of EMT and fibrosis. Sildenafil attenuates the parenchymal remodeling however it is not effective in reducing VSMC hypertrophy in combined group.. CPFE is characterized by heterogenous parenchymal remodeling and differential caveolin-1 expression. Sildenafil therapy attenuates parenchymal pathologies in CPFE. Additional therapy is however needed for attenuating VSMC remodeling.

Topics: Animals; Bleomycin; Caveolin 1; Cigarette Smoking; Collagen; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelial Cells; Fibroblasts; Gene Expression Regulation; Humans; Lung; Male; Mesenchymal Stem Cells; Phosphodiesterase 5 Inhibitors; Pulmonary Emphysema; Pulmonary Fibrosis; Rats; Rats, Wistar; Reactive Oxygen Species; Sildenafil Citrate; Xanthine Oxidase

Silicosis is a lethal pneumoconiosis disease characterized by chronic lung inflammation and fibrosis. The present study was to explore the effect of against crystalline silica (CS)-induced pulmonary fibrosis. A total of 138 wild-type C57BL/6J mice were divided into control and experimental groups, and killed on month 0, 1, 2, 3, 4, and 5. Different doses of N-acetylcysteine (NAC) were gavaged to the mice after CS instillation to observe the effect of NAC on CS induced pulmonary fibrosis and inflammation. The pulmonary injury was evaluated with Hematoxylin and eosin/Masson staining. Reactive oxygen species level was analyzed by DCFH-DA labeling. Commercial ELISA kits were used to determine antioxidant activity (T-AOC, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) and cytokines (TNF-α, IL-1β, IL-4, and IL-6). The expression of oxidising enzymes (NOX2, iNOS, SOD2, and XO) were detected by real time PCR. Immunohistochemistry (IHC) staining was performed to examine epithelial-mesenchymal transition-related markers. The mice treated with NAC presented markedly reduced CS-induced pulmonary injury and ameliorated CS-induced pulmonary fibrosis and inflammation. The level of malondialdehyde was reduced, while the activities of GSH-PX, SOD, and T-AOC were markedly enhanced by NAC. We also found the down-regulation of oxidising enzymes (NOX2, iNOS, SOD2, and XO) after NAC treatment. Moreover, E-cadherin expression was increased while vimentin and Cytochrome C expressions were decreased by NAC. These encouraging findings suggest that NAC exerts pulmonary protective effects in CS-induced pulmonary fibrosis and might be considered as a promising agent for the treatment of silicosis.

Topics: Acetylcysteine; Administration, Oral; Animals; Antioxidants; Crystallization; Disease Models, Animal; Female; Gene Expression Regulation; Glutathione Peroxidase; Interleukin-1beta; Interleukin-4; Interleukin-6; Lung; Mice; Mice, Inbred C57BL; NADPH Oxidase 2; Nitric Oxide Synthase Type II; Oxidative Stress; Pulmonary Fibrosis; Reactive Oxygen Species; Silicon Dioxide; Silicosis; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood.. To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung.. Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid.. Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor.. Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.

Topics: Allopurinol; Animals; Biomarkers; Bleomycin; Bronchoalveolar Lavage Fluid; Carrier Proteins; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Interleukin-1beta; Lung; Lung Injury; Mice; Myeloid Differentiation Factor 88; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia; Pulmonary Fibrosis; Uric Acid

The present study aimed to examine the antioxidant properties of Houttuynia cordata (HC) and its protective effect on bleomycin-induced pulmonary fibrosis in rats. Results showed that aqueous extract of HC exhibited a different magnitude of antioxidant activities in all model systems tested. Although HC showed weaker free radical scavenging and xanthine oxidase inhibitory activity than vitamin E, its anti-lipid peroxidation activity in rat liver homogenate was close to that of vitamin E. In animal studies, HC significantly decreased the levels of superoxide dismutase, malondialdehyde, hydroxyproline, interferon-gamma, and tumor necrosis factor-alpha. However, an increase in the concentration of catalase was noted in the bronchoalveolar lavage fluid. HC also remarkably improved the morphological appearance of the lung of bleomycin-treated rats. These results suggest that HC possesses a protective effect against bleomycin-induced pulmonary fibrosis. Interestingly, this protective effect was more pronounced than that of vitamin E. In conclusion, the protective effect of HC on pulmonary fibrosis could be partly associated with the reduction of oxidative damage caused by bleomycin.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Bronchoalveolar Lavage Fluid; Catalase; Drugs, Chinese Herbal; Free Radical Scavengers; Houttuynia; Hydroxyproline; Interferon-gamma; Lipid Peroxidation; Liver; Male; Malondialdehyde; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Xanthine Oxidase

In 25 children with lymphoblastic leukemia is shown that prophylactic treatment with allopurinol, 48 hours before initial cytostatic therapy, always prevents hyperuricemia. In 4 patients was renounced on this measurement and 2 of 4 patients died of the sequeles of hyperuricemia. In severe ill leukemic patients the parental use of allopurinol is recommended. 2 additional patients developed during remission therapy or after cessation of chemotherapy a moderate hyperuricemia which had to be treated, over years, with allopurinol.

Topics: Adolescent; Allopurinol; Asparaginase; Child; Humans; Leukemia, Lymphoid; Male; Methylprednisolone; Pentamidine; Pulmonary Fibrosis; Uric Acid; Vincristine

Topics: Allopurinol; Amenorrhea; Busulfan; Chlorambucil; Chronic Disease; Drug Eruptions; Female; Hemolysis; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukocytosis; Lymphocytosis; Prednisolone; Pulmonary Fibrosis; Splenectomy; Vincristine