Tumor necrosis factor-α induced protein 6 attenuates acute lung injury following paraquat exposure

Context: Paraquat exposure commonly occurs in the developing countries and the mortality rate is high. However, there is currently no consensus on the efficacy of treatment for paraquat exposure.

Objective: The study was aimed to explore the effects of tumor necrosis factor-α (TNF-α) induced protein 6 (TSG-6) on acute lung injury (ALI) following paraquat exposure in rats.

Materials and methods: Male Sprague–Dawley (SD) rats were randomly divided into the sham group (n?=?8), the paraquat group (n?=?8), and the paraquat TSG-6-treated group (n?=?8). Rats were administered with 50?mg/kg of paraquat intraperitoneally. At 1?h after exposure, rats were treated with 30?μg of recombinant human TSG-6 (rhTSG-6) intraperitoneally. After 6?h of exposure, ALI scores were evaluated by histology and the expression of pro-inflammatory cytokines in lung was assayed using real-time RT-PCR.

Results: ALI scores were significantly lower in the paraquat TSG-6-treated group, compared with the paraquat group (p?<?0.05). The expression of interleukin (IL)-1β, IL-6, and TNF-α mRNA was significantly lower in the paraquat TSG-6-treated group, compared with the paraquat group (p?<?0.01, respectively).

Discussion and conclusion: Administration of rhTSG-6 attenuates ALI following paraquat exposure by suppressing inflammatory response.     

MS80, a novel sulfated oligosaccharide,inhibits pulmonary fibrosis by targeting TGF-β1 both in vitro and in vivo

Aim:

The pro-fibrogenic cytokine transforming growth factor-beta 1 (TGF-β1) has attracted much attention for its potential role in the etiology of idiopathic pulmonary fibrosis (IPF). Here, we demonstrate that MS80, a novel sulfated oligosaccharide extracted from seaweed, can bind TGF-β1. The aim of the present study was to determine whether MS80 is capable of combating TGF-β1-mediated pulmonary fibrotic events both in vitro and in vivo, and to investigate the possible underlying mechanisms.

Methods:

Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-β. MTT assay, flow cytometry, Western blot analysis, BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80. The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model.

Results:

We report that MS80, a new kind of sulfated oligosaccharide extracted from seaweed, inhibits TGF-β1-induced pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis in vivo. Our results indicated that MS80 competitively inhibited heparin/HS-TGF-β1 interaction through its high binding affinity for TGF-β1. Moreover, MS80 arrested TGF-β1-induced human embryo pulmonary fibroblast (HEPF) cell proliferation, collagen deposition and matrix metalloproteinase (MMP) activity. Intriguingly, MS80 deactivated both the ERK and p38 signaling pathways. MS80 was also a potent suppressor of bleomycin-induced rat pulmonary fibrosis in vivo, as evidenced by improved pathological settings and decreased lung collagen contents.

Conclusion:

MS80 in particular, and perhaps oligosaccharide in general, offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.     

MS80, a novel sulfated oligosaccharide,inhibits pulmonary fibrosis by targeting TGF-β1 both in vitro and in vivo

Aim： The pro-fibrogenic cytokine transforming growth factor-beta 1 （TGF-β1） has attracted much attention for its potential role in the etiology of idiopathic pulmonary fibrosis （IPF）. Here, we demonstrate that MS80, a novel sulfated oligosaccharide extracted from seaweed, can bind TGF-β1. The aim of the present study was to determine whether MS80 is capable of combating TGF-β1-mediated pulmonary fibrotic events both in vitro and in vivo, and to investigate the possible underlying mechanisms.
Methods： Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-β. MTI- assay, flow cytometry, Western blot analysis, BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80. The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model. Results： We report that MS80, a new kind of sulfated oligosaccharide extracted from seaweed, inhibits TGF-β1-induced pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis in vivo. Our results indicated that MS80 competitively inhibited heparin/ HS-TGF-β1 interaction through its high binding affinity for TGF-β1. Moreover, MS80 arrested TGF-β1-induced human embryo pulmonary fibroblast （HEPF） cell proliferation, collagen deposition and matrix metalloproteinase （MMP） activity. Intriguingly, MS80 deactivated both the ERK and p38 signaling pathways. MS80 was also a potent suppressor of bleomycin-induced rat pulmonary fibrosis in vivo, as evidenced by improved pathological settings and decreased lung collagen contents.
Conclusion： MS80 in particular, and perhaps oligosaccharide in general, offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.     

Ergothioneine protects against neuronal injury induced by β-amyloid in mice

β-Amyloid peptides (Aβ) are neurotoxic and contribute to the development of Alzheimer’s disease (AD). Ergothioneine (EGT) has been shown to protect against loss of memory and learning abilities in mice. In this study, mice were orally fed EGT (0.5 or 2 mg/kg body weight) for 16 days before treatment (i.c.v) with a single dose of Aβ1–40 in the hippocampus. After resting for 12 days to restore the body weight, the mice were again fed EGT for additional 39 days. Active avoidance tests were conducted on days 37–39 (short-memory avoidance) and on days 37, 44 and 51 (long-memory avoidance). Water maze task was used to evaluate learning and memory abilities by acquisition test and retention test. In both long-memory avoidance and water maze tests, EGT significantly decreased the escape latency and increased the frequency of successful avoidance. Furthermore, EGT significantly prevented Aβ accumulation in the hippocampus and brain lipid peroxidation, restored acetylcholinesterase (AChE) activity, maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of Aβ1–40-teated mice. Thus, EGT can protect against Aβ-induced loss of memory and learning abilities in mice. Further studies are required to confirm the protective effects of EGT on the development or progression of AD.     

Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?

There is compelling evidence that uncontrolled activation of the coagulation cascade following lung injury contributes to the development of lung inflammation and fibrosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and fibrotic lung disease. This article reviews our current understanding of the mechanisms leading to the activation of the coagulation cascade in response to lung injury and the evidence that excessive procoagulant activity is of pathophysiological significance in these disease settings. Current evidence suggests that the tissue factor-dependent extrinsic pathway is the predominant mechanism by which the coagulation cascade is locally activated in the lungs of patients with ALI/ARDS and pulmonary fibrosis. Whilst, fibrin deposition might contribute to the pathophysiology of ALI/ARDS following systemic insult; current evidence suggests that the cellular effects mediated via activation of proteinase-activated receptors (PARs) may be of particular importance in influencing inflammatory and fibroproliferative responses in experimental models involving direct injury to the lung. In this regard, studies in PAR(1) knockout mice have shown that this receptor plays a major role in orchestrating the interplay between coagulation, inflammation and lung fibrosis. This review will focus on our current understanding of excessive procoagulant signalling in acute and chronic lung injury and will highlight the novel opportunities that this may present for therapeutic intervention.     

Artesunate affords protection against aspirin–induced gastric injury by targeting oxidative stress and proinflammatory signaling

Background

Prolonged use of aspirin, a commonly prescribed non steroidal anti-inflammatory drug, is well known to produce gastrointestinal toxicity which could be minimized by various anti-secretory agents. The present study was carried out to evaluate the protective effect of artesunate against aspirin induced gastric injury in rats.

Salidroside protects against diabetes mellitus-induced kidney injury and renal fibrosis by attenuating TGF-β1 and Wnt1/3a/β-catenin signalling

This study evaluated if the nephroprotective effect of Salidroside in type 1 diabetes mellitus (T1DM) involves modulation of Wnt/β-catenin signalling pathways. Control or Streptozotocin (STZ, 50 mg/kg, iv)-induced T1DM adult male Wister rats were treated with the vehicle and Salidroside (100 mg/kg, orally) for 8 weeks daily. As compared to T1DM-induced rats, Salidroside improved kidney structure, reduced urinary protein and albumin level, increased creatinine clearance, and suppressed renal fibrosis. It also decreased mRNA and protein levels of Wnt1, Wnt3, and TGF-β1, phosphorylation of Smad-3, total and nuclear levels of β-catenin, and levels and activities of cleaved caspase-3. Concomitantly, Salidroside significantly increased the levels of p-β-catenin (Ser^33/37/Thr⁴¹) and suppressed protein levels of Axin-2, fibronectin, and, mRNA and protein levels of collagen IIIa, the main targets of β-catenin. In both control and T1DM rats, Salidroside significantly lowered fasting glucose levels and reduced renal levels of reactive oxygen species (ROS) p-and GS3Kβ (Ser9) but significantly increased levels of SOD and GSH. In conclusion, Salidroside protected the kidney of rats against T1DM-induced injury and fibrosis by activating GS3Kβ-induced inhibition of Wnt1/Wnt3a β-catenin. This was associated with hypoglycaemic and antioxidant effects.     

Anti-inflammatory effects of N-Acetylcysteine and Elaeagnus angustifolia extract on acute lung injury induced by λ-carrageenan in rat

Inflammopharmacology - N-Acetylcysteine (NAC) is a chemical compound with anti-inflammatory and antioxidant activity and acts as a free radical scavenger. Elaeagnus angustifolia (EA) is a plant...     

Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise?

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TGF-β1 as a therapeutic target for pulmonary fibrosis and COPD

TGF-β1 is a multifunctional molecule that is expressed in an exaggerated fashion during injury, inflammation and repair. Its expression is dysregulated in lung tissues from patients with pulmonary fibrosis and chronic obstructive pulmonary disease. In animal models, introduction of TGF-β1 expression in the lung causes prominent tissue fibrosis and alveolar destruction. On the other hand, the exaggerated production of TGF-β1, an inability to activate TGF-β1 or a block in TGF-β1 signaling have all been associated with the development of emphysematous pulmonary lesions. A number of studies have demonstrated that TGF-β1 is a major player in the pathogenesis of pulmonary fibrosis and emphysema. In this review, we discuss how TGF-β1 expression is regulated and mechanistically related to the development of tissue fibrosis and emphysema in experimental animal models and humans. We further highlight potential therapeutic options that control TGF-β1-associated genes or signals to restore extracellular matrix homeostasis in which TGF-β1 plays a central role.     

Angiotensin receptor type 1 antagonists protect against neuronal injury induced by oxygen�Cglucose depletion

BACKGROUND AND PURPOSE

Several clinical trials and in vivo animal experiments have suggested that blockade of angiotensin receptor type 1 (AT₁) improves ischaemic outcomes. However, the mechanism(s) underlying these effects has not been elucidated. Here, we have investigated the protective effects of pretreatment with AT₁ receptor antagonists, losartan or telmisartan, against ischaemic insult to neurons in vitro.

EXPERIMENTAL APPROACH

Primary rat neuron–astrocyte co-cultures and astrocyte-defined medium (ADM)-cultured pure astrocyte cultures were prepared. Ischaemic injury was modelled by oxygen–glucose depletion (OGD) and lactate dehydrogenase release after OGD was measured with or without AT₁ receptor antagonists or agonists (L162313), AT₂ receptor antagonist (PD123319) or agonist (CGP-42112A) pretreatment, for 48 h. Activity of glutamate transporter 1 (GLT-1) was evaluated by [³H]-glutamate uptake assays, after AT₁ receptor agonists or antagonists. Immunoblot and real-time PCR were used for analysis of protein and mRNA levels of GLT-1.

KEY RESULTS

AT₁ receptor agonists augmented OGD-induced cellular damage, which was attenuated by AT₁ receptor antagonists. AT₁ receptor antagonists also suppressed OGD-induced extracellular glutamate release, reactive oxygen species production and nitric oxide generation. GLT-1 expression and glutamate uptake activity were significantly enhanced by AT₁ receptor antagonists and impaired by AT₁ receptor agonists. AT₁ receptor stimulation suppressed both ADM-induced GLT-1 protein expression and mRNA levels. AT₁b receptor knock-down with siRNA enhanced GLT-1 expression. In postnatal (P1–P21) rat brains, protein levels of GLT-1 and AT₁ receptors were inversely correlated.

CONCLUSIONS AND IMPLICATIONS

Suppression of AT₁ receptor stimulation induced GLT-1 up-regulation, which ameliorated effects of ischaemic injury.     

Urotensin Ⅱ accelerates cardiac fibrosis and hypertrophy of rats induced by isoproterenol1

AIM: To study whether urotensin II (UII), a potent vasoconstrictive peptide, is involved in the development of cardiac hypertrophy and fibrogenesis of rats induced by isoproterenol (ISO). METHODS: Thirty male Wistar rats were randomly divided into 3 groups. Group 1 was the healthy control group, group 2 was the ISO group, and group 3 was the ISO+UII group. In groups 2 and 3, ISO (5 mg x kg(-1) x d(-1)) was given (sc) once daily for 7 d. Group 3 was also given UII in the first day [3 nmol/kg (5 microg/kg), iv], followed by sc (1.5 microg/kg) twice daily. Group 1 received 0.9% saline. UII receptor (UT) mRNA expression was determined by RT-PCR. The contents of UII and angiotensin II (Ang II) were determined by radioimmunoassay. In vitro, the effects of UII on DNA/collagen synthesis of cardiac fibroblasts were determined by [3H]thymidine/[3H]proline incorporation. RESULTS: The ratio of heart weight/body weight, plasma lactate dehydrogenase activity, myocardial malondialdehyde and hydroxyproline concentration increased significantly in the ISO group, as well as UT mRNA expression, plasma and cardiac UII and ventricular Ang II, compared with the control group (P< 0.01). ISO induced significant myocardial fibrogenesis. Moreover, UII+ISO co-treatment significantly increased the changes of biochemical markers of injury and the degree of cardiac hypertrophy and fibrosis. In vitro, 5 x 10(-9 )-5 x 10(-7 ) mol/L UII stimulated [3H]thymidine/[3H] proline incorporation into cardiac fibroblasts in a dose-dependent manner (P< 0.01). CONCLUSION: These results suggest that UII was involved in the development of cardiac fibrosis and hypertrophy by synergistic effects with ISO.     

Aspirin enhances protective effect of fish oil against thrombosis and injury‐induced vascular remodelling

Background and Purpose

Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti‐inflammatory and cardio‐protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury.

Experimental Approach

Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical‐ and ferric chloride‐induced carotid artery thrombosis were employed to evaluate platelet function.

Key Results

FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX‐1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury‐induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co‐administration of FO and aspirin decreased the expression of pro‐inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro‐resolution lipid mediator‐Resolvin E1, was significantly elevated in plasma in FO/aspirin‐treated mice.

Conclusions and Implications

Co‐administration of FO and low‐dose aspirin may act synergistically to protect against thrombosis and injury‐induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

AA

arachidonic acid

CO

coconut oil

CVD

cardiovascular disease

DHA

docosahexaenoic acid

EPA

eicosapentaenoic acid

FO

fish oil

HDLC

high‐density lipoprotein cholesterol

LDLC

low‐density lipoprotein cholesterol

PCI

percutaneous coronary intervention

PUFA

polyunsaturated fatty acid; TG, triglyceride

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Hydrogen sulfide protects against bleomycin-induced pulmonary fibrosis in rats by inhibiting NF-κB expression and regulating Th1/Th2 balance

Hydrogen sulfide (H₂S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. The objective of this study was to evaluate the inhibitory effect of H₂S on bleomycin (BLM)-induced pulmonary fibrosis in rats and its possible mechanisms. Fifty-four pathogen-free Male Wistar rats were randomly divided into three groups: control, BLM and H₂S treated groups with 18 rats in each group. Each group was then divided into three subgroups based on time of study (7, 14 and 28 day). Pulmonary fibrosis model was established by a single intratracheal instillation of BLM A₅ (5 mg/kg). While control rats received saline, rats of the treated group simultaneously were administered intraperitoneal injections of NaHS (the H₂S donor, 28 μmol/kg) once daily. BLM induced pulmonary inflammation and fibrosis, increased lung hydroxyproline levels, lung index, total cell counts, neutrophils and eosinophils counts and expression of NF-κB p65 in lung tissue, decreased lymphocytes and macrophages counts. In addition, Th1 response is suppressed as shown by diminished IFN-γ in bronchoalveolar lavage fluid (BALF) after BLM exposure, and enhancement of Th2 response is marked by increased IL-4 in BALF. H₂S administration significantly attenuated these effects. The findings reveal the therapeutic potential of H₂S for BLM-induced pulmonary fibrosis in male rats, which were at least partly due to inhibition NF-κB p65 expression and regulation of Th1/Th2 balance.     

Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NFκ-B activation and proinflammatory cytokine production

Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of proinflammatory cytokine like tumor necrosis factor alpha (TNF-α) and activation of nuclear factor kappa-B (NFκ-B) may strongly intensify inflammation and cell damage. Additionally, reactive oxygen species (ROS) also exerts significant effect in this whole cell signaling machinery. The present study was designed to investigate the protective effects of perillyl alcohol (POH) on ethanol-induced acute liver injury in Wistar rats and its probable mechanism. We have successfully demonstrated that pre-treatment with POH, besides exerting antioxidant activity might be able to modulate TNF-α release and NFκ-B activation. Rats were divided into five groups and treated with ethanol or POH via an intragastric tube for one week. Control group was treated with vehicle, and ethanol treated group was given ethanol (5 g/kg body wt). Animal of treatment groups were pretreated with POH (50 & 100 mg/kg body wt) and have been given ethanol. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase and hepatic malondialdehyde were increased significantly by ethanol treatment. Ethanol administration decreased hepatic reduced glutathione content and various antioxidant enzymes activity. TNF-α production and NFκ-B activation was also found to be increased after ethanol administration. POH pre-treatment significantly ameliorates ethanol induced acute liver injury possibly by inhibition of lipid peroxidation, replenishment of endogenous enzymatic and non-enzymatic defense system, downregulation of TNF-α as well as NFκ-B.     

Modulation of lung inflammation by surfactant and nitric oxide in E coli-induced septic acute lung injury in piglets

BACKGROUND: Septic lung injury results in intractable respiratory failure and surfactant and nitric oxide (NO) may protect the lungs from injury by suppression of inflammatory process. AIM: To establish a piglet model of acute lung injury (ALI) induced by Escherichia coli peritonitis and investigates anti-inflammation mechanisms of combined surfactant and inhaled nitric oxide (iNO) treatment. METHODS: Thirty piglets (body weight 6-9 kg) were randomly allocated to either a normall group (N, n=6) with only intraperitoneal injection of normal sodium or groups with intraperitoneal injection E coli at 5×10~9 cfu.mL.kg~(-1) (n=6 each) followed by treatment with (1) control (C), (2) iNO at 10 ppm (NO), (3) surfactant at 100 mg/kg (Surf), (4) both surfactant and iNO (SNO). Arterial blood gas, dynamic lung compliance (C_(dyn)), resistance of respiratory system (Rrs), mean system arterial pressure, and heart rate were measured at baseline, establishment of ALl, every 2 h during the treatment. Blood routine, meth