A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age

Moitra, Jaideep; Evenoski, Carrie; Sammani, Saad; Wadgaonkar, Raj; Turner, Jerrold R.; Fan, Shwu; Garcia, Joe G.N.

doi:10.1016/j.trsl.2007.12.008

Cited by 33 publications

(51 citation statements)

References 65 publications

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“…Consistent with these observations, mice with a targeted deletion of nmMLCK exhibited in vivo protection from lipopolysaccharide (LPS)-induced ALI and VILI (11). In addition, we recently generated genetically engineered mice that overexpressed nmMLCK targeted to the vascular endothelium, resulting in a marked exaggeration of LPS-induced and VILIinduced lung injury in a sex-specific and age-specific manner (12). Finally, previous case-control association studies also highlighted the capacity of genetic variants (single-nucleotide polymorphisms, or SNPs) within MYLK, the gene encoding nmMLCK, in contributing to the susceptibility to sepsis and ALI, as well as to severe asthma in African Americans (13)(14)(15).…”

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confidence: 63%

Non–Muscle Myosin Light Chain Kinase Isoform Is a Viable Molecular Target in Acute Inflammatory Lung Injury

Mirzapoiazova¹,

Moitra²,

Moreno‐Vinasco³

et al. 2011

Am J Respir Cell Mol Biol

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110

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Acute lung injury (ALI) and mechanical ventilator-induced lung injury (VILI), major causes of acute respiratory failure with elevated morbidity and mortality, are characterized by significant pulmonary inflammation and alveolar/vascular barrier dysfunction. Previous studies highlighted the role of the non-muscle myosin light chain kinase isoform (nmMLCK) as an essential element of the inflammatory response, with variants in the MYLK gene that contribute to ALI susceptibility. To define nmMLCK involvement further in acute inflammatory syndromes, we used two murine models of inflammatory lung injury, induced by either an intratracheal administration of lipopolysaccharide (LPS model) or mechanical ventilation with increased tidal volumes (the VILI model). Intravenous delivery of the membrane-permeant MLC kinase peptide inhibitor, PIK, produced a dose-dependent attenuation of both LPS-induced lung inflammation and VILI (z50% reductions in alveolar/vascular permeability and leukocyte influx). Intravenous injections of nmMLCK silencing RNA, either directly or as cargo within angiotensin-converting enzyme (ACE) antibody-conjugated liposomes (to target the pulmonary vasculature selectively), decreased nmMLCK lung expression (z70% reduction) and significantly attenuated LPS-induced and VILI-induced lung inflammation (z40% reduction in bronchoalveolar lavage protein). Compared with wild-type mice, nmMLCK knockout mice were significantly protected from VILI, with significant reductions in VILI-induced gene expression in biological pathways such as nrf2-mediated oxidative stress, coagulation, p53-signaling, leukocyte extravasation, and IL-6-signaling. These studies validate nmMLCK as an attractive target for ameliorating the adverse effects of dysregulated lung inflammation.

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mentioning

confidence: 63%

Non–Muscle Myosin Light Chain Kinase Isoform Is a Viable Molecular Target in Acute Inflammatory Lung Injury

Mirzapoiazova¹,

Moitra²,

Moreno‐Vinasco³

et al. 2011

Am J Respir Cell Mol Biol

Self Cite

110

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“…BAL was performed by flushing the lungs with 5 ml of cold Hanks' balanced salt solution (Invitrogen, Grand Island, NY) via the tracheal cannula, as previously described (16). Total cells were counted with a hemacytometer.…”

Section: Accumulation Of Bal Protein and Leukocyte Quantificationmentioning

confidence: 99%

“…Protein concentrations in BAL fluid were measured using an RC DC Protein Assay (Bio-Rad, Hercules, CA), as previously described (16,17). Sample readings (optical density) were converted to mg/ml, using albumin as standard (0.1-1.5 mg/ml).…”

Section: Measurements Of Bal Total Protein Albumin and Concentratiomentioning

confidence: 99%

A Sphingosine 1–Phosphate 1 Receptor Agonist Modulates Brain Death–Induced Neurogenic Pulmonary Injury

Sammani

Park

Zaidi

et al. 2011

Am J Respir Cell Mol Biol

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Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (z 50% reduction, P ¼ 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.Keywords: neurogenic pulmonary edema; lung injury; sphingosine 1-phosphate; sphingolipids; lung transplant donors Over the past decade, lung transplantation has become an increasingly important mode of therapy for patients with a variety of endstage lung diseases. The vast majority of lung donors are individuals with brain death (BD). However, the early autonomic storm accompanying brain BD triggers the development of systemic and pulmonary inflammatory responses, which lead to increased pulmonary endothelial permeability (1, 2) and to the sympathetic vasoconstriction of the systemic and pulmonary vasculature. These changes, in addition to possible ischemiareperfusion injury, disrupt the integrity of the alveolar capillary membrane, resulting in neurogenic pulmonary edema (NPE) (1-4). Increased pulmonary interstitial and alveolar fluid accumulation usually develops rapidly after acute injury to the central nervous system (1), and any preventive treatment should be given early after BD (3). This lung injury mimics a form of acute respiratory distress syndrome (ARDS), the most devastating form of acute lung injury (ALI), with excessive ...

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“…18 In addition, up-regulation of the nmMLCK isoform is observed in lung tissues obtained from asthmatic patients where asthma is characterized by chronic inflammation of the airway, 19 underscoring the important role played by nmMLCK in various inflammatory lung diseases. 5,7,[14][15][16][17][18][19] The exact signaling mechanisms that result in enhanced nmMLCK expression and activation are poorly understood. Vascular endothelial growth factor (VEGF) is a proangiogenic glycoprotein that is essential for a variety of cellular processes, including angiogenesis, cell proliferation, and cell migration.…”

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confidence: 99%

Sp1‐Mediated Nonmuscle Myosin Light Chain Kinase Expression and Enhanced Activity in Vascular Endothelial Growth Factor–Induced Vascular Permeability

et al. 2015

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Despite the important role played by the nonmuscle isoform of myosin light chain kinase (nmMLCK) in vascular barrier regulation and the implication of both nmMLCK and vascular endothelial growth factor (VEGF) in the pathogenesis of acute respiratory distress syndrome (ARDS), the role played by nmMLCK in VEGF-induced vascular permeability is poorly understood. In this study, the role played by nmMLCK in VEGF-induced vascular hyperpermeability was investigated. Human lung endothelial cell barrier integrity in response to VEGF is examined in both the absence and the presence of nmMLCK small interfering RNAs. Levels of nmMLCK messenger RNA (mRNA), protein, and promoter activity expression were monitored after VEGF stimulation in lung endothelial cells. nmMYLK promoter activity was assessed using nmMYLK promoter luciferase reporter constructs with a series of nested deletions. nmMYLK transcriptional regulation was further characterized by examination of a key transcriptional factor. nmMLCK plays an important role in VEGFinduced permeability. We found that activation of the VEGF signaling pathway in lung endothelial cells increases MYLK gene product at both mRNA and protein levels. Increased nmMLCK mRNA and protein expression is a result of increased nmMYLK promoter activity, regulated in part by binding of the Sp1 transcription factor on triggering by the VEGF signaling pathway. Taken together, these findings suggest that MYLK is an important ARDS candidate gene and a therapeutic target that is highly influenced by excessive VEGF concentrations in the inflamed lung.

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A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age

Cited by 33 publications

References 65 publications

Non–Muscle Myosin Light Chain Kinase Isoform Is a Viable Molecular Target in Acute Inflammatory Lung Injury

Non–Muscle Myosin Light Chain Kinase Isoform Is a Viable Molecular Target in Acute Inflammatory Lung Injury

A Sphingosine 1–Phosphate 1 Receptor Agonist Modulates Brain Death–Induced Neurogenic Pulmonary Injury

Sp1‐Mediated Nonmuscle Myosin Light Chain Kinase Expression and Enhanced Activity in Vascular Endothelial Growth Factor–Induced Vascular Permeability

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