thiourea and Pulmonary-Fibrosis

The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor-induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow-derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.

Topics: Animals; Bleomycin; Cell Line; Cell Movement; Cell Proliferation; Humans; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Protein Kinase Inhibitors; Pulmonary Fibrosis; Quinolines; Receptor, Macrophage Colony-Stimulating Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Thiourea

To explore therapeutic effects and underlying mechanism of Salubrinal combined with Ulinastatin (UTI) on acute Paraquat (PQ) poisoning. Four hundred rats were randomly allocated into UTI group, SAL group, SAL + UTI and control group according to random number table with 100 rats in each group. Acute PQ poisoning models were established, and all rats received UTI, Salubrinal, SAL + UTI and normal saline injection, respectively. Afterward, we analyzed the change of lung tissue and explored the mechanism. Acute PQ poisoning caused significantly damage in rat lung tissue structure, and UTI could effectively repair lung tissue damage. Salubrinal suppressed hemorrhage and fibrosis, but promoted inflammatory infiltration. In contrast, UTI + Salubrinal suppressed hemorrhage, fibrosis and inflammatory infiltration, but could not improve lung tissue damage. Expression of LC3 and Bcl-2 showed statistically significant difference among different groups (p < 0.05). LC3 and Bcl-2 levels in UTI group were much higher than in the other groups, and LC3 and Bcl-2 levels in UTI + SAL group was second higher. LC expression in SAL group was lower than in UTI group and UTI + SAL group with Bcl-2 in control group significantly lower than in the other groups (p < 0.05). Expression of Caspase-3 and Bcl-2/Bax in lung tissue in different groups had statistically significant difference (p < 0.05). Caspase-3 in UTI group was lower than in the other groups; however, Bcl-2/Bax in UTI group was higher than in the other groups (p < 0.05). Acute PQ poisoning can cause endoplasmic reticulum stress-autophagy in rat, and UTI can increase Bcl-2 expression, decrease Caspase-3, which can inhibit progress of lung injury by suppressing apoptosis and exert good therapeutic effects. Although salubrinal has marked effects on protecting lung tissue, it can increase Bcl-2 expression, which is not beneficial to lung tissue protection. The underlying mechanism still needs further exploration.

Topics: Animals; Cinnamates; Cytokines; Drug Combinations; Drug Interactions; Female; Glycoproteins; Herbicides; Paraquat; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Thiourea; Treatment Outcome; Trypsin Inhibitors

A mouse model of hypersensitivity pneumonitis was generated by challenge with a thermophilic actinomycete. Oxygen radical scavengers were administered to challenged mice: vitamin E at 1000 units daily, polyethylene glycol-superoxide dismutase (SOD) at 500 units daily, polyethylene glycol-catalase at 10,000 units daily, 1,3,dimethyl-2-thiourea (DMTU) at 2 mg daily, and the biomimetic SOD, copper(II) [diisopropyl salicylate]2 (CuDIPS) at 1 mg daily. At three weeks after actinomycete challenge, a 10-fold increase in bronchoalveolar (BAL) cell number was observed. Treatments with catalase or DMTU were without effect on the BAL cell number in challenged mice. However, infusion of vitamin E was associated with an increased BAL cell influx (15-fold increase at two and three weeks). Similarly, treatment with PEG-SOD and CuDIPS resulted in an increase in cell number at two and three weeks. PEG-SOD or CuDIPS treatment resulted in a strong neutrophilia, whereas control challenged mice had a cellular influx mostly of macrophages and lymphocytes. Vitamin E treatment of challenged mice led to an increased T lymphocyte recruitment at two and three weeks. In vitro studies showed that actinomycete challenge was associated with an enhancement of alveolar macrophage O2- release, which was blocked by PEG-SOD, vitamin E, or DSC treatment but was unaffected by catalase or DMTU treatment. In control challenged mice, there was a 25-fold increase in the BAL albumin concentration at two weeks. PEG-SOD, vitamin E, or CuDIPS treatment all decreased the albumin concentration; the three modulators also diminished lung fibrosis at two or three weeks, as seen by a decrease in lung hydroxyproline and collagen synthesis by lung fibroblasts. Examination of sections from lungs of challenged animals showed evidence of cellular infiltrates around the bronchi and the blood vessels. Challenged mice given continuous infusions of vitamin E, SOD, or CuDIPS had lung histological scores that were significantly lower than control challenged mice or challenged mice treated with catalase or DMTU. Thus, therapies based on O2- scavenging or treatment with a general antioxidant such as vitamin E may hold some promise in the treatment of hypersensitivity pneumonitis.

Topics: Animals; Antigens, Fungal; Antioxidants; Bronchoalveolar Lavage Fluid; Collagen; Farmer's Lung; Fibroblasts; Free Radical Scavengers; Hydroxyproline; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Micromonosporaceae; Neutrophils; Pulmonary Fibrosis; Reactive Oxygen Species; Salicylates; Specific Pathogen-Free Organisms; Superoxide Dismutase; T-Lymphocytes; Thiourea; Vitamin E

Small dosages of endotoxin (100--500 micrograms/kg) provide significant protection against the acute manifestations of pulmonary O2 toxicity and lethality. Ninety-seven percent of endotoxin-treated adult rats survived a 72-h exposure to greater than or equal to 95% O2 with mimimal lung changes, compared to 32% of control animals (P less than 0.01). Exposure to greater than or equal to 95% O2 for 7 days resulted in a 20% survival rate in untreated control rats vs. 98% survival in endotoxin-treated rats (P LESS THan 0.01). Histological evaluation of lung from survivors revealed substantially less collagen and reticular fiber deposition in the endotoxin-treated animal lungs. Endotoxin treatment was associated with increased activity of the protectant antioxidant enzyme systems of the lung in an apparent dose-response manner. Endotoxin's protective activity against O2 toxicity does not appear to depend on an initial toxic insult to the lung like with alpha-naphthylthiourea, oleic acid, or alloxan treatment. The data support a protective role for endotoxin against the acute and the more chronic manifestations of O2-induced pulmonary injury.

Topics: Alloxan; Animals; Dose-Response Relationship, Drug; Endotoxins; Hemorrhage; Lung Diseases; Oleic Acids; Oxygen; Pulmonary Edema; Pulmonary Fibrosis; Rats; Thiourea

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hematocrit; Hypoproteinemia; Lung; Male; Naphthalenes; Pleural Effusion; Pulmonary Alveoli; Pulmonary Edema; Pulmonary Fibrosis; Rats; Recurrence; Rodenticides; Tachyphylaxis; Thiourea