Effect of tyrosine kinase inhibitors, imatinib and nilotinib, in murine lipopolysaccharide-induced acute lung injury during neutropenia recovery

Kim, In Kyoung; Rhee, Chin Kook; Yeo, Chang Dong; Kang, Hyeon Hui; Lee, Dong Gun; Lee, Sang Haak; Kim, Jin Woo

doi:10.1186/cc12786

Cited by 35 publications

(40 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, imatinib potently suppressed TNF-␣ production and NF-B signaling in macrophages/monocytes stimulated with LPS (61). At the whole animal level, imatinib inhibited the production of cytokines such as IL-6 and attenuated the development of pulmonary edema in a neutropenic model of LPS-induced lung injury and in bleomycin-induced ALI (32,51). The anti-inflammatory effects of imatinib also were evident in a murine model of asthma (5) and in a Bcr-Abl-transfected hematopoietic cell line (4).…”

Section: Discussionmentioning

confidence: 80%

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Letsiou

Rizzo

Sammani

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and antiinflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.

show abstract

Section: Discussionmentioning

confidence: 80%

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Letsiou

Rizzo

Sammani

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…Post-treatment with the selective Src-tyrosine kinase inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo [3,4-d]-pyrimidine (PP1) after intratracheal instillation of LPS led to reductions in total protein content in BALF, neutrophil recruitment, nuclear factor (NF)-κB activation, and levels of TNF-α [29]. Treatment with imatinib or nilotinib in LPS-instilled mice during recovery from neutropenia attenuated pulmonary edema, histological changes, and concentrations of TNF-α, IL-1β, IL-6, and myeloperoxidase in BALF [30].…”

Section: Discussionmentioning

confidence: 99%

“…Although advances in supportive care and ventilator management for human ARDS have reduced short-term mortality [2], effective pharmacological therapies are still lacking. In this context, recent studies evaluated the role of tyrosine kinase inhibitors in experimental ARDS [3][4][5]. As major therapeutic agents in oncology, these pharmacological agents block the action of different classes of protein tyrosine kinases (PTKs), important molecules that regulate many intracellular signaling pathways, including the acute inflammatory response to different stimuli [6].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

Oliveira

Silva

Marques

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. Methods: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. Results: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.

show abstract

“…The Abl family kinases, c-Abl (Abl1) and A bl r elated g ene (Arg, Abl2), have recently emerged as key mediators of vascular permeability due to their well characterized roles in the dynamic regulation of the actin cytoskeleton and cell-cell and cell-matrix junctions 5–8 . Several groups have recently reported that the FDA approved Abl kinase inhibitor imatinib attenuates vascular leak induced by thrombin, histamine, vascular endothelial growth factor (VEGF), lipopolysaccharide (LPS), and oxidative stress 9–13 . Although the mechanisms are not fully characterized, it is clear that Abl kinase inhibition has potent and pleiotropic effects on vascular barrier function.…”

Section: Inflammatory Vascular Leak: Overviewmentioning

confidence: 99%

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

Rizzo

Aman

Amerongen

et al. 2015

ATVB

View full text Add to dashboard Cite

The vascular endothelium separates circulating fluid and inflammatory cells from the surrounding tissues. Vascular leak occurs in response to wide-spread inflammatory processes, such as sepsis and Acute Respiratory Distress Syndrome (ARDS), due to the formation of gaps between endothelial cells (EC). Although these disorders are leading causes of mortality in the ICU, no medical therapies exist to restore EC barrier function. Recent evidence highlights a key role for the Abl family of non-receptor tyrosine kinases in regulating vascular barrier integrity. These kinases have well-described roles in cancer progression and neuronal morphogenesis, but their functions in the vasculature have remained enigmatic until recently. The Abl family kinases, c-Abl (Abl1) and Abl related gene (Arg, Abl2), phosphorylate several cytoskeletal effectors that mediate vascular permeability, including myosin light chain kinase, cortactin, vinculin, and β-catenin. They also regulate cell-cell and cell-matrix junction dynamics, and the formation of actin-based cellular protrusions in multiple cell types. Additionally, both c-Abl and Arg are activated by hyperoxia and contribute to oxidant-induced EC injury. These numerous roles of Abl kinases in EC and the current clinical usage of imatinib and other Abl kinase inhibitors have spurred recent interest in repurposing these drugs for the treatment of vascular barrier dysfunction. This review will describe the structure and function of Abl kinases with an emphasis on their roles in mediating vascular barrier integrity. We will also provide a critical evaluation of the potential for exploiting Abl kinase inhibition as a novel therapy for inflammatory vascular leak syndromes.

show abstract

Effect of tyrosine kinase inhibitors, imatinib and nilotinib, in murine lipopolysaccharide-induced acute lung injury during neutropenia recovery

Cited by 35 publications

References 38 publications

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology

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

Contact Info

Product

Resources

About