Targeting Abl Kinases to Regulate Vascular Leak During Sepsis and Acute Respiratory Distress Syndrome

Rizzo, Alicia N.; Aman, Jurjan; Amerongen, Geerten P. van Nieuw; Dudek, Steven M.

doi:10.1161/atvbaha.115.305085

Cited by 69 publications

(82 citation statements)

References 85 publications

(117 reference statements)

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“…21,32 Although c-Abl kinase is best known for it´s role in human leukemias, 20,33 accumulating data suggest that c-Abl exerts more pluripotent functions in different inflammatory conditions, such as endotoxemic lung damage, Ig-mediated renal injury, and nephrotoxicity. 25,26,34 In the present study, we could demonstrate that targeting c-Abl kinase with a specific inhibitor (GZD824) reduced c-Abl phosphorylation in both circulating neutrophils and in the pancreas of animals with AP. In order to define the contribution of neutrophils to the c-Abl kinase activity in the inflamed pancreas, animals were depleted of neutrophils.…”

Section: Discussionsupporting

confidence: 51%

“…It is widely accepted that c‐Abl kinase is a critical signaling molecule regulating cellular actin dynamics and cytoskeletal rearrangement . Although c‐Abl kinase is best known for it´s role in human leukemias, accumulating data suggest that c‐Abl exerts more pluripotent functions in different inflammatory conditions, such as endotoxemic lung damage, Ig‐mediated renal injury, and nephrotoxicity . In the present study, we could demonstrate that targeting c‐Abl kinase with a specific inhibitor (GZD824) reduced c‐Abl phosphorylation in both circulating neutrophils and in the pancreas of animals with AP.…”

Section: Discussionmentioning

confidence: 46%

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c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis

Madhi

Rahman

Mörgelin³

et al. 2019

Journal of Leukocyte Biology

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Neutrophil extracellular traps (NETs) are involved in acute pancreatitis (AP) but mechanisms controlling NET expulsion in AP are incompletely understood. Herein, we examined the role of c‐Abelson (c‐Abl) kinase in NET formation and tissue damage in severe AP. AP was induced by taurocholate infusion into pancreatic duct or intraperitoneal administration of l‐arginine in mice. Pancreatic, lung, and blood samples were collected and levels of phosphorylated c‐Abl kinase, citrullinated histone 3, DNA‐histone complexes, myeloperoxidase, amylase, cytokines, and CXC chemokines were quantified. Citrullinated histone 3, reactive oxygen species (ROS), and NET formation were determined in bone marrow neutrophils. Taurocholate challenge increased phosphorylation of c‐Abl kinase and levels of citrullinated histone 3 in the pancreas as well as DNA‐histone complexes in the plasma. Administration of the c‐Abl kinase inhibitor GZD824 not only abolished activation of c‐Abl kinase but also decreased levels of citrullinated histone 3 in the pancreas and DNA‐histone complexes in the plasma of animals with AP. Moreover, GZD824 decreased plasma levels of amylase, IL‐6, and MMP‐9 as well as edema, acinar cell necrosis, hemorrhage, CXC chemokine formation, and neutrophil infiltration in the inflamed pancreas. A beneficial effect of c‐Abl kinase inhibition was confirmed in l‐arginine‐induced pancreatitis. In vitro, inhibition of c‐Abl kinase reduced TNF‐α‐induced formation of ROS, histone 3 citrullination, and NETs in isolated bone marrow neutrophils. Our findings demonstrate that c‐Abl kinase regulates NET formation in the inflamed pancreas. In addition, inhibition of c‐Abl kinase reduced pancreatic tissue inflammation, and damage in AP. Thus, targeting c‐Abl kinase might be a useful way to protect the pancreas in severe AP.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 46%

c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis

Madhi

Rahman

Mörgelin³

et al. 2019

Journal of Leukocyte Biology

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“…It is unlikely that the reduction in LPS‐induced pulmonary edema which we observed in imatinib‐treated mice is wholly due to a decrease in pulmonary apoptosis, but imatinib has been reported to improve pulmonary vascular barrier dysfunction induced by a variety of injurious stimuli (Rizzo et al. ).…”

Section: Discussionmentioning

confidence: 84%

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice

et al. 2015

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Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS-induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS-induced lung oxidant injury as measured by γ-H2AX, a marker of oxidant-induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram-negative sepsis and sepsis-induced ARDS.

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“…49 Several cancer drugs such as Gleevac (Imatinib)-a tyrosine kinase inhibitor, activate autophagy and reduce inflammatory responses. 50 Doxycycline has potential for protection against destruction and degradation of tissue collagen and other structural proteins through its matrix metallo proteinase (MMP) inhibitor effect. 51 A recent study describes a library of 290 compounds screened for antiviral activity against MERS-CoV and severe acute respiratory syndrome coronavirus (SARS-CoV).…”

Section: Repurposed Drugsmentioning

confidence: 99%

Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections

Zumla

Azhar

Arabi

et al. 2015

International Journal of Infectious Diseases

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Three years after its first discovery in Jeddah Saudi Arabia, the novel zoonotic pathogen of humans, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) continues to be a major threat to global health security.(1) Sporadic community acquired cases of MERS continue to be reported from the Middle East. The recent nosocomial outbreaks in hospitals in Seoul, Korea and at the National Guard Hospital in Riyadh, Saudi Arabia indicate the epidemic potential of MERS-CoV. Currently there are no effective anti-MERS-CoV anti-viral agents or therapeutics and MERS is associated with a high mortality rate (40%) in hospitalised patients. A large proportion of MERS patients who die have a range of pulmonary pathology ranging from pneumonia to adult respiratory distress syndrome with multi-organ failure, compounded by co-morbidities, reflecting a precarious balance of interactions between the host-immune system and MERS-CoV. Whilst we wait for new MERS-CoV specific drugs, therapeutics and vaccines to be developed, there is a need to advance a range of Host-Directed Therapies. A range of HDTs are available, including commonly used drugs with good safety profiles, which could augment host innate and adaptive immune mechanisms to MERS-CoV, modulate excessive inflammation and reduce lung tissue destruction. We discuss the rationale and potential of using Host-Directed Therapies for improving the poor treatment outcomes associated with MERS. Carefully designed randomized controlled trials will be needed to determine whether HDTs could benefit patients with MERS. The recurrent outbreaks of MERS-CoV infections at hospitals in the Middle East present unique opportunities to conduct randomized clinical trials. The time has come for a more coordinated global response to MERS and a multidisciplinary global MERS-CoV response group is required to take forward priority research agendas.

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Targeting Abl Kinases to Regulate Vascular Leak During Sepsis and Acute Respiratory Distress Syndrome

Cited by 69 publications

References 85 publications

c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis

c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice

Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections

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