Azithromycin does not improve disease severity in acute experimental pancreatitis

Weis, Sebastian; Heindl, Mario; Carvalho, Tânia; Jentho, Elisa; Lorenz, Jana; Sommerer, Ines; Mössner, Joachim; Hoffmeister, Albrecht

doi:10.1371/journal.pone.0216614

Cited by 4 publications

(3 citation statements)

References 34 publications

(35 reference statements)

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“…This is also one of the well-established methods for IHC quantification in several publications. [57][58][59][60] We have been trying to quantify by using staining intensity or IDO value. However, because chondrocytes only accounts for around 5% of the cartilage area, it would bring us much background signal for quantification.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Sun

Crawford

et al. 2023

CARTILAGE

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Objective Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase–activating protein, Leukotriene A4 hydrolase (LTA4H) and its downstream product LTB4. The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB4 pathway in OA disease progression. Design Both clinical human cartilage samples ( n = 7) and mice experimental OA models ( n = 6) were used. The levels of LTA4H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA4H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes. Results We found that both LTA4H and LTB4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA4H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA4H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan ( ACAN), collagen 2A1 ( COL2A1), and SRY-Box transcription factor 9 ( SOX9). Conclusions Our results indicate that the LTA4H pathway is a crucial regulator of OA pathogenesis and suggest that LTA4H could be a therapeutic target in combat OA.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Sun

Crawford

et al. 2023

CARTILAGE

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“…Weis et al 41 in their experimental work on mice confirmed that the prophylactic use of macrolide antibiotics does not reduce the severity of the disease in the course of acute pancreatitis and does not reduce the migration of cytokines to the pancreatic tissue in the acute stage of the disease (Table 1). Numerous studies have confirmed that the use of antibiotics only in the case of infected necrosis can have the benefit of inhibiting or reducing the systemic inflammatory cascade in acute pancreatitis.…”

Section: Experimental Treatmentmentioning

confidence: 95%

Treatment of Microcirculatory Disturbances in Acute Pancreatitis

Antkowiak¹,

Białecki²,

Chabowski³

et al. 2022

Pancreas

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Acute pancreatitis is a serious inflammatory condition. Research has shown an increase in the number of pancreatitis-associated hospitalizations, with a marked decline in the mortality rates down to 0.79% in patients with acute pancreatitis and 0.26% in patients with exacerbation of chronic pancreatitis. Up to one-third of patients develop pancreatic tissue necrosis, with a mortality rate of 30%. One of the mechanisms is the disturbances in pancreatic microcirculation due to the release of endothelin, a long-acting vasoconstrictor. The development of pancreatitis causes the release of other inflammatory mediators, which reduce blood flow in the microcirculation. The activation of intracellular trypsinogen initiates a cascade of mechanisms in pancreatitis. There is no specific treatment for acute pancreatitis. Protease inhibitors are not effective in treating severe acute pancreatitis. There is an important role of low-molecular-weight heparin in attenuating necrosis and restoring perfusion of the pancreas. Other drugs used are endothelin receptor antagonists, antagonist of interleukin-1 and interleukin-6 receptors, α-tocopherol, tumor necrosis factor-α and platelet-activating factor inhibitors, acetylsalicylic acid, and local intra-arterial injection of lidocaine. The prophylactic use of antibiotics is not recommended. The treatment outcome of acute pancreatitis is still unsatisfactory.

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“…In mice, an AP can be induced as mild or severe form depending on number and days of CN injections [27]. In our study, AP was induced using an adapted mouse model of CN-induced mild acute pancreatitis, as previously described [28][29][30][31][32]. Prior to injection of CN or saline, mice were fasted for 14-16 h with free access to water.…”

Section: Animal Experimentsmentioning

confidence: 99%

Glyoxalase-I Is Upregulated in Acute Cerulein-Induced Pancreatitis: A New Mechanism in Pancreatic Inflammation?

Hollenbach¹,

Sonnenberg²,

Sommerer³

et al. 2021

Antioxidants

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Inflammation caused by oxidative stress (ROS) demonstrates an essential mechanism in the pathogenesis of acute pancreatitis (AP). Important sources for ROS comprise the reactive compound methylglyoxal (MGO) itself and the MGO-derived formation of advanced glycation end-products (AGEs). AGEs bind to the transmembrane receptor RAGE and activate NF-κB, and lead to the production of pro-inflammatory cytokines. MGO is detoxified by glyoxalase-I (Glo-I). The importance of Glo-I was shown in different models of inflammation and carcinogenesis. Nevertheless, the role of Glo-I and MGO in AP has not been evaluated so far. This study analyzed Glo-I in cerulein-(CN)-induced AP and determined the effects of Glo-I knockdown, overexpression and pharmacological modulation. Methods: AP was induced in C57BL6/J mice by i.p. injection of CN. Glo-I was analyzed in explanted pancreata by Western Blot, qRT-PCR and immunohistochemistry. AR42J cells were differentiated by dexamethasone and stimulated with 100 nM of CN. Cells were simultaneously treated with ethyl pyruvate (EP) or S-p-bromobenzylglutathione-cyclopentyl-diester (BrBz), two Glo-I modulators. Knockdown and overexpression of Glo-I was achieved by transient transfection with Glo-I siRNA and pEGFP-N1-Glo-I-Vector. Amylase secretion, TNF-α production (ELISA) and expression of Glo-I, RAGE and NF-κB were measured. Results: Glo-I was significantly upregulated on protein and mRNA levels in CN-treated mice and AR42J cells. Dexamethasone-induced differentiation of AR42J cells increased the expression of Glo-I and RAGE. Treatment of AR42J cells with CN and EP or BrBz resulted in a significant reduction of CN-induced amylase secretion, NF-κB, RAGE and TNF-α. Overexpression of Glo-I led to a significant reduction of CN-induced amylase levels, NF-κB expression and TNF-α, whereas Glo-I knockdown revealed only slight alterations. Measurements of specific Glo-I activity and MGO levels indicated a complex regulation in the model of CN-induced AP. Conclusion: Glo-I is overexpressed in a model of CN-induced AP. Pharmacological modulation and overexpression of Glo-I reduced amylase secretion and the release of pro-inflammatory cytokines in AP in vitro. Targeting Glo-I in AP seems to be an interesting approach for future in vivo studies of AP.

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Azithromycin does not improve disease severity in acute experimental pancreatitis

Cited by 4 publications

References 34 publications

Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Treatment of Microcirculatory Disturbances in Acute Pancreatitis

Glyoxalase-I Is Upregulated in Acute Cerulein-Induced Pancreatitis: A New Mechanism in Pancreatic Inflammation?

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Azithromycin does not improve disease severity in acute experimental pancreatitis

Cited by 4 publications

References 34 publications

Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Treatment of Microcirculatory Disturbances in Acute Pancreatitis

Glyoxalase-I Is Upregulated in Acute Cerulein-Induced Pancreatitis: A New Mechanism in Pancreatic Inflammation?

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Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis

Inhibition of Leukotriene A₄ Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis