scholarly journals Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model

2021 ◽  
Vol 22 (17) ◽  
pp. 9612
Author(s):  
Josep Bringué ◽  
Raquel Guillamat-Prats ◽  
Maria Luisa Martinez ◽  
Eva Torrents ◽  
Marta Camprubí-Rimblas ◽  
...  

Background: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. Objective: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. Methods and main results: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. Conclusion: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Pamela K. Sari ◽  
Poppy M. Lintong ◽  
Lily L. Loho

Abstract: Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone endogenous testosterone that stimulates anabolic (protein synthesis) and androgenic effects (masculinization). Long-term usage of AAS can result in liver damage. However, physiological concentrations of testosterone can stimulate protein synthesis which lead to an increase in muscle size, body mass, and endurance. This study aimed to determine the histopathology of liver and skeletal muscles of wistar rats that were given low dose and high dose injection of AAS. Subjects were 21 wistar rats divided into 7 groups. Group A was given standard pellets for 56 days (negative control), terminated on days 29,43, and 57. Group B was treated with low-dose AAS injection and standard pellets for 28 days, terminated on day 29. Group C was treated with low-dose AAS injection and standard pellets for 42 days, terminated on day 43. Group D was treated with low-dose AAS injection and standard pellets for 56 days, terminated on day 57. Group E was treated with high-dose AAS injection and standard pellets for 28 days, terminated on day 29. Group F was treated with high-dose AAS injection and standard pellets for 42 days, terminated on day 43. Group G was treated with high-dose AAS injection and standard pellets for 56 days, terminated on day 57. The results showed that the histopathology of liver and muscles in group A was still normal. In group B, the architecture of liver was still normal with a few inflammatory cells around the Kiernan triangle while in muscle the ratio of myofibril diameter was 1.28:1. In group C and group D, there were widening of the hepatic artery, bile duct, and portal vein containing blood fibrin, and inflammatory cells around the Kiernan triangle. The ratio of myofibril diameter was 1.43:1 in group C and 2.14:1 in group D. In group E, F and G, there were micro-vesicular fatty cells in the peripheral part of the liver meanwhile the myofibril diameter ratio of the muscles in group E was 1.43:1, group F 2.1:1, and group G 2.28:1. Conclusion: Administration of AAS injection of low dose and high dose for less than 4 weeks could result in inflammation, dilation of the portal vein, hepatic artery and bile duct meanwhile administration of AAS for over 4 weeks could ressult in focal fatty liver (steatosis). The administration of AAS injection of low dose and high dose for 4,6 and 8 weeks reslutid in enlargement of skeletal muscle (muscle hypertrophy).Keywords: androgenic-anabolic steroids, liver, skeletal muscleAbstrak: Anabolik Androgenik Steroid (AAS) adalah derivat sintetis dari hormon sex testosteron endogen pria, yang merangsang efek anabolik (sintesis protein) dan androgenik (maskulinisasi). Penggunaan AAS jangka panjang dapat mengakibatkan terjadinya kerusakan hati namun secara fisiologi testosteron dapat menstimulasi sintesis protein sehinggaberdampak pada peningkatan ukuran otot, massa tubuh dan ketahanan tubuh. Penelitian ini bertujuan untuk mengetahui gambaran histopatologi hati dan otot rangka wistar yang diberikan AAS injeksi dosis rendah dan dosis tinggi. Subjek penelitian 21 ekor wistar yang dibagi menjadi 7 kelompok. Kelompok A diberi pelet standar selama 56 hari (kontrol negatif), terminasi pada hari ke-29, 43, dan 57. Kelompok B diberi perlakuan AAS injeksi dosis rendah dan pelet standar selama 28 hari, terminasi hari ke-29. Kelompok C diberi AAS injeksi dosis rendah dan pelet standar selama 42 hari, terminasi hari ke-43. Kelompok D diberi AAS injeksi dosis rendah dan pelet standar selama 56 hari, terminasi hari ke-57. Kelompok E diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 28 hari, terminasi hari ke-29. Kelompok F diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 42 hari, terminasi hari ke-43. Kelompok G diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 56 hari, terminasi hari ke-57. Hasil penelitian menunjukkan pada kelompok A didapatkan gambaran histopatologi hati normal sedangkan pada otot tidak terdapat perubahan. Pada kelompok B didapatkan arsitektur hati masih normal dengan sedikit sel radang disekitar segitiga Kiernan sedangkan pada otot terlihat diameter miofibril ratio 1,28:1. Pada kelompok C dan D terlihat pelebaran arteri hepatika, duktus biliaris, dan vena porta yang berisi fibrin darah, serta sel-sel radang di sekitar segitiga Kiernan. Pada kelompok C diameter miofibril ratio 1,43;1 dan pada kelompok D 2,14:1. Pada kelompok E, F dan G terdapat sel-sel perlemakan mikrovesikuler di perifer sedangkan pada otot diameter miofibril ratio kelompok E 1,43:1, kelompok F 2,1:1, dan kelompok G 2,28:1. Simpulan: Pada pemberian AAS injeksi dosis rendah dan dosis tinggi kurang dari 4 minggu terjadi peradangan hati, pelebaran vena porta, arteri hepatika dan duktus biliaris sedangkan lebih dari 4 minggu terdapat perlemakan (steatosis) fokal hati. Pemberian AAS injeksi dosis rendah dan tinggi dalam waktu 4,6 dan 8 minggu menunjukkan pembesaran otot rangka (hipertrofi otot).Kata kunci: AAS, hati, otot rangka


Author(s):  
Karen Courville ◽  
Norman Bustamante ◽  
Maydelin Pecchio

Coronavirus infection produces a cytokine storm in some patients, developing a moderate to severe clinical condition that is associated to increased mortality mainly because of severe pulmonary involvement. Elevated levels of IL-6 have been found in non-survivor patients. In these patients, clearance of cytokines with extracorporeal therapies, Pulse High- Volume Hemofiltration together with adsorption columns Cytosorb, in short periods of time for 1 to 3 days, could help remove inflammatory cytokines allowing a downregulation of the inflammatory response; and, at the same time, treatment with low dose steroids, could give an opportunity for the host to reach homeostasis, decreasing lung damage and improving survival.


2021 ◽  

Background: Sepsis is most likely to cause lung damage in patients, and the detection rate and mortality rate are high. Here, we investigated the expression of miR-20a in sepsis-induced acute lung injury (ALI) rats and its effect on inflammatory response, and reveal its possible molecular mechanism. Method: The model of acute lung injury caused by sepsis in rats was established by cecal ligation and puncture. The expression of miR-20a in lung tissue was determined by RT-qPCR. Acute lung injury rats were injected with 5 nmol miR-20a agomir or agomir NC every day for 3 days. Rats were sacrificed by arterial bleeding and lung tissues were removed. Serum interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE staining was used to observe the pathology of lung tissue and calculate the pathological score of lung injury. Western blot to determine the level of TLR4 and nuclear transcription factor κB p65 (NF-κB p65) protein in lung tissue. The luciferase reporter assay was used to verify the binding effect of miR-20a on the 3 non-coding TLR4. Results: We found that compared with that in Normal group, the expression of miR-20a in lung tissues of rats with ALI was decreased (p < 0.05). In miR-20a agomir group, the plasma level of IL-1β, IL-6, and TNF-α was significantly lower than that in agomir NC group and ALI group (p < 0.05), while higher than those in Normal group (p < 0.05). The HE staining results showed that the pathological score of lung injury in rats in miR-20a agomir group was lower than that of agomir NC group and ALI group (p < 0.05). Compared with agomir NC group and ALI group, the expression of TLR4 and NF-κB p65 in miR-20a agomir group was decreased (p < 0.01). The luciferase reporting experiment confirmed that TLR4 was a target gene of miR-20a. Conclusion: To sum up, miR-20a exerts a protective effect on sepsis-induced ALI rats through its anti-inflammatory effect. The targeting of TLR4 by miR-20a may be an effective method to reduce the inflammatory response in sepsis-induced ALI.


2005 ◽  
Vol 7 (26) ◽  
pp. 1-16 ◽  
Author(s):  
Francis Gigliotti ◽  
Terry W. Wright

Pneumocystis carinii pneumonia (PCP) is a life-threatening infection that occurs in immunocompromised individuals, particularly those with advanced human immunodeficiency virus (HIV) infection. Interestingly, morbidity and mortality is related to the underlying cause of immunosuppression, with AIDS patients faring better than oncology patients for example. In addition, the prognosis of PCP has been correlated with markers of inflammation rather than with organism numbers. There is now increasing evidence that lung damage occurring during PCP is a result of the type and extent of the host inflammatory response to P. carinii rather than a result of direct damage by the organism. This review will discuss the experimental and clinical data demonstrating how the host-mediated inflammatory response to infection with P. carinii determines the ultimate outcome of PCP. A better understanding of the pathophysiology of PCP should lead to the development of improved therapies for the treatment of PCP.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Sara Kasirzadeh ◽  
Mohammad Hossein Ghahremani ◽  
Neda Setayesh ◽  
Fereshteh Jeivad ◽  
Amir Shadboorestan ◽  
...  

Purpose. Sepsis originates from the host inflammatory response, especially to bacterial infections, and is considered one of the main causes of death in intensive care units. Various agents have been developed to inhibit mediators of the inflammatory response; one prospective agent is β-sitosterol (βS), a phytosterol with a structure similar to cholesterol. This study is aimed at evaluating the effects of βS on the biomarkers of inflammation and liver function in cecal ligation and puncture- (CLP-) induced septic rats. Methods. Thirty male Wistar rats were divided equally into six groups as follows: sham, CLP, CLP+dexamethasone (DX, 0.2 mg/kg), CLP+βS (1 mg/kg), CLP+imipenem (IMI, 20 mg/kg), and CLP+IMI (20 mg/kg)+βS (1 mg/kg). Serum levels of IL-1β, IL-6, IL-10, AST, ALT, and liver glutathione (GSH) were assessed by ELISA. Liver expression levels of TNF-α and NF-κBi mRNAs were evaluated by RT-qPCR. Results. Serum concentrations of IL-1β, IL-6, IL-10, ALT, and AST and mRNA levels of TNF-α and NF-κBi were all significantly higher in septic rats than in normal rats ( p < 0.05 ). Liver GSH content was markedly lower in the CLP group than that in the sham group. βS-treated rats had remarkably lower levels of IL-1β, IL-6, IL-10, TNF-α, NF-κBi, AST, and ALT (51.79%, 62.63%, 41.46%, 54.35%, 94.37%, 95.30%, 34.87%, and 46.53% lower, respectively) and greater liver GSH content (35.71% greater) compared to the CLP group ( p < 0.05 ). Conclusion. βS may play a protective role in the septic process by mitigating inflammation. This effect is at least partly mediated by inhibition of the NF-κB signaling pathway. Thus, βS can be considered as a supplementary treatment in septic patients.


2020 ◽  
Vol 11 ◽  
Author(s):  
Daniella Bianchi Reis Insuela ◽  
Maximiliano Ruben Ferrero ◽  
Diego de Sá Coutinho ◽  
Marco Aurélio Martins ◽  
Vinicius Frias Carvalho

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE2 and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ2 (15d-PGJ2) while from LOXs are the LXA4 and LXB4. In different models of asthma, PGE2, 15d-PGJ2, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts in vitro. In addition, PGE2, 15d-PGJ2, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype in vitro and in vivo. Although PGE2 and LXA4 showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE2 caused side effects, while LXA4 presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.


Clinics ◽  
2007 ◽  
Vol 62 (3) ◽  
pp. 321-326 ◽  
Author(s):  
Naomi K. Nakagawa ◽  
José Jukemura ◽  
Priscila Aikawa ◽  
Rafael A. Nogueira ◽  
Luiz F. Poli-de-Figueiredo ◽  
...  

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Silvanus Olu Innih ◽  
Ikechi Gerald Eze ◽  
Kingsley Omage

Abstract Background Momordica. charantia is popularly used as a medicinal herb in ethnomedicine for the management of cardiovascular diseases. In this study, we evaluated the beneficial effects of the ethanolic extract of M. charantia (Linn.) in experimentally induced cardiovascular disorders using cholesterol-fed Wistar rat. Methods Seventy-two experimental rats were randomly assigned into nine 9 groups of 8 rats each and treated as follows: Rats in group A (control) were given distilled water only; Rats in group B were given 30 mg/kg of cholesterol dissolved in coco-nut oil (cholesterol solution); Rats in group C were given cholesterol solution and 100 mg/kg Atorvastatin; Rats in group D were given 250 mg/kg of M. charantia and cholesterol solution; Rats in group E were given 500 mg/kg of M. charantia and cholesterol solution; Rats in group F were given 250 mg/kg. M. charantia; Rats in group G were given 500 mg/kg M. charantia; Rats in group H were given 1 ml of coconut oil; Rats in group I were given 100 mg/kg of Atorvastatin. Results Mean LDL-cholesterol was significantly (P < 0.05) lower in groups F, E and H as compared with the control groups. Histological analysis of the heart and aortic branch of the experimental rats show that cholesterol administration induced myocardial degeneration, vascular ulceration and stenosis in the aorta and heavy perivascular infiltrates of inflammatory cells. However, these deleterious effects were ameliorated upon treatment with Momordica charantia and Atorvastatin as compared with the control groups. Conclusion Our findings indicate the possible cardiovascular benefits of M. charantia.


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