Glycogen Synthase Kinase-3β Inhibition Attenuates the Development of Bleomycin-Induced Lung Injury

Cuzzocrea, Salvatore; Genovese, Tiziana; Mazzon, Emanuela; Esposito, Emanuela; Muià, Carmelo; Abdelrahman, Maha; Paola, Rosanna Di; Bramantı, Placido; Thiemermann, Christoph

doi:10.1177/039463200702000320

Cited by 19 publications

(9 citation statements)

References 36 publications

(40 reference statements)

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“…The effects of treatments on the plasma level of IL-6, an indicator of systemic inflammation, followed the same pattern. These results are in marked contrast to other reports on the anti-inflammatory activity of this GSK inhibitor in lung tissue in the context of carrageenan-and bleomycin-induced lung injury [5,6]. However, these effects were observed after several hours or days, and different treatment regimes were used.…”

Section: Discussioncontrasting

confidence: 96%

Inhibition of glycogen synthase kinase-3β prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung

Waldow

Witt

Matschke

2010

Clinical Hemorheology and Microcirculation

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Recent studies on the mechanisms of ischemic preconditioning in myocardial tissue have presented convincing evidence that multiple protective pathways converge on inhibition of glycogen synthase kinase-3␤ (GSK-3␤). To directly address the role of GSK-3␤ in ischemia and reperfusion (I/R) of the lung, a rat model of left lung in situ ischemia was used. The specific non-competitive inhibitor of GSK-3␤, TDZD-8, was injected (3 mg/kg, vehicle in controls) 5 min before the left lung hilum was occluded for 60 min. Animals in the ischemia group underwent the same treatment, but without administration of TDZD-8. Lung functional and biochemical parameters were determined at time points 15 min and 60 min reperfusion. Treatment with TDZD-8 improved gas exchange (arterial pO 2 ), but I/R-induced inflammation (plasma interleukin-6, leukocyte invasion) was not affected. The I/R cycle induced a rapid (15 min reperfusion) increase of protein tyrosine phosphorylation, including the activating phosphorylation of focal adhesion kinase at Tyr397, Tyr407, Tyr577, and Tyr861, and the non-receptor kinase Src at Tyr416. The phosphorylation was blocked by the GSK inhibitor. This effect may be related to the reduced plasma level of the strong effector of focal adhesion kinase, transforming growth factor-␤1, in the TDZD group. The underlying mechanisms are elusive, but they deserve further investigation, especially in relation to the early increase of lung permeability in this rat model of I/R injury. In conclusion, the results suggest that inhibition of GSK-3␤ improves rat lung function during an I/R cycle, but only during the early reperfusion phase.

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Section: Discussioncontrasting

confidence: 96%

Inhibition of glycogen synthase kinase-3β prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung

Waldow

Witt

Matschke

2010

Clinical Hemorheology and Microcirculation

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“…Cuzzocrea and colleagues have reported similar findings in a collagen-induced arthritis model using type II collagen and complete Freund’s Adjuvant [117]. Mice given a GSK3 inhibitor exhibited reduced paw edema, reduced weight loss, attenuated production of inflammatory mediators, and suppressed bone erosion, as compared to control mice [116]. The broad-spectrum influence of GSK3 inhibition on the inflammatory response was demonstrated using an EAE mouse model [125].…”

Section: Gsk3 and Its Role In The Adaptive Immune Systemmentioning

confidence: 82%

Glycogen synthase kinase 3: A point of convergence for the host inflammatory response

2011

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The phosphatidylinositol 3-kinase (PI3K) pathway has been shown to play a central role in regulating the host inflammatory response. Recent studies characterizing the downstream effector molecules within the PI3K pathway have identified that the serine/threonine kinase, glycogen synthase kinase 3 (GSK3), plays a pivotal role in regulating the production of pro-and antiinflammatory cytokines. In innate immune cells, GSK3 inactivation augments anti-inflammatory cytokine production while concurrently suppressing the production of pro-inflammatory cytokines. The role of GSK3 in T cell biology has also been studied in detail and is involved in regulating multiple downstream signaling processes mediated by the T cell receptor (TCR), the costimulatory molecule CD28, and the IL-17 receptor. In vivo studies assessing the therapeutic properties of GSK3 inhibitors have shown that the inactivation of GSK3 can protect the host from immune-mediated pathology and death. This review will highlight the immunological importance GSK3 plays within different signal transduction pathways of the immune system, the cellular mechanisms regulating the activity of GSK3, the role of GSK3 in innate and adaptive immune responses, and the in vivo use of GSK3 inhibitors to treat inflammatory mediated diseases in animals.

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“…Streptomyces verticillus -derived bleomycin, used in the treatment of various cancers, can induce lung injury. In a murine model, bleomycin-induced pulmonary inflammation, characterized by neutrophil infiltration, edema and the accumulation of inflammatory mediators (myeloperoxidase, iNOS, TNF and IL-1β), is dramatically reduced upon GSK3β inhibition by TDZD8 [87]. …”

Section: Exploitation Of Gsk3β and Related Molecules By Pathogenic Bamentioning

confidence: 99%

GSK3β and the control of infectious bacterial diseases

Wang

Kumar

Lamont

et al. 2014

Trends in Microbiology

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Glycogen synthesis kinase 3β (GSK3β) has been shown to be a critical mediator of the intensity and direction of the innate immune system responding to bacterial stimuli. This review will focus on: (i) the central role of GSK3β in the regulation of pathogen-induced inflammatory responses through the regulation of pro- and anti-inflammatory cytokine production. (ii) The extensive ongoing efforts to exploit GSK3β for its therapeutic potential in the control of infectious diseases. (iii) The increasing evidence that specific pathogens target GSK3β-related pathways for immune evasion. A better understanding of complex bacterial–GSK3β interactions is likely to lead to more effective anti-inflammatory interventions and novel targets to circumvent pathogen colonization and survival.

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Glycogen Synthase Kinase-3β Inhibition Attenuates the Development of Bleomycin-Induced Lung Injury

Cited by 19 publications

References 36 publications

Inhibition of glycogen synthase kinase-3β prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung

Inhibition of glycogen synthase kinase-3β prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung

Glycogen synthase kinase 3: A point of convergence for the host inflammatory response

GSK3β and the control of infectious bacterial diseases

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