EphA2 Receptor Signaling Mediates Inflammatory Responses in Lipopolysaccharide-Induced Lung Injury

Hong, Ji Young; Shin, Mi Hwa; Chung, Kyung Soo; Kim, Eun Young; Jung, Ji Ye; Kang, Young Ae; Kim, Young Sam; Kim, Se Kyu; Chang, Joon; Park, Moo Suk

doi:10.4046/trd.2015.78.3.218

Cited by 19 publications

(16 citation statements)

References 30 publications

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“…Many previous studies demonstrate that endothelial EphA2 expression is enhanced and activated during inflammatory contexts, including within the endothelium overlying atherosclerotic plaques 6, 9, 33 . Using the Apoe -/- model of atherogenesis, we now demonstrate that EphA2 deletion reduced atherosclerotic burden associated with reduced inflammation in the early plaque.…”

Section: Discussionmentioning

confidence: 99%

“…EphA2 expression is enhanced in a variety of proinflammatory conditions, including atherosclerosis, acute lung injury, ischemia/reperfusion, and psoriasis 6, 33-35 , often concomitant with upregulation of its ligand ephrinA1. During early atherogenesis, endothelial activation promotes NF-κB-dependent ICAM-1 and VCAM-1 expression to facilitate leukocyte recruitment and extravasation 36, 37 .…”

Section: Discussionmentioning

confidence: 99%

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EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis

et al. 2017

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Background Atherosclerotic plaque formation results from chronic inflammation and fibroproliferative remodeling in the vascular wall. We previously demonstrated that both human and mouse atherosclerotic plaques show elevated expression of EphA2, a guidance molecule involved in cell-cell interactions and tumorigenesis. Methods Here, we assessed EphA2's role in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe-/-) and by assessing EphA2 function in multiple vascular cell culture models. Following 8-16 weeks Western diet, male and female mice were assessed for atherosclerotic burden in the large vessels, and plasma lipid levels were analyzed. Results Despite enhanced weight gain and plasma lipid levels compared to Apoe-/- controls, EphA2-/-Apoe-/- knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. While plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2-/-Apoe-/- mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression following smooth muscle transition to a synthetic phenotype, and EphA2 depletion reduces smooth muscle proliferation, mitogenic signaling, and extracellular matrix deposition both in atherosclerotic plaques and in vascular smooth muscle cells in culture. Conclusions Together these data identify a novel role for EphA2 in atherosclerosis, regulating both plaque inflammation and progression to advanced atherosclerotic lesions. Cell culture studies suggest that endothelial EphA2 contributes to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas smooth muscle EphA2 expression may regulate the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis

et al. 2017

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“…EphA2 antagonism reduced the expression of phospho-p85, phosphoinositide 3-kinase 110gamma, phosphoAkt, NF-kB, and proinflammatory cytokines, and inhibited the phosphoinositide 3-kinase-Akt pathway [48]. Furthermore, a role for EphB2 was described during B cell activation in which EphB2 was involved in human naive B cell activation via the Src-p65 and Notch1 signaling pathways and could be regulated by miR-185.…”

Section: Ngps [ 4 7 3 _ T D $ D I F F ] Expressed In Endothelial Cellsmentioning

confidence: 97%

Immunomodulatory Functions of Neuronal Guidance Proteins

Mirakaj

Rosenberger

2017

Trends in Immunology

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“…LPS SE is, however, the main inducer of sepsis-related ARDS. As such, many studies have used LPS from E. coli to elucidate the details of endotoxin-induced lung injury [201][202][203][204][205][206][207][208][209][210][211][212][213][214][215][216][217][218].…”

Section: Escherichia Colimentioning

confidence: 99%

“…LPS EC can contribute to the pathogenesis of ALI and ARDS [37,[188][189][190], characterized by infiltration of neutrophils and macrophages, the release of pro-inflammatory mediators such as IL-1β, IL-6, IL-8/CXCL8, IL-18, IL-23, TNF, and MIP-2, the decreased release of anti-inflammatory cytokines such as IL-4 and IL-10, and the disruption of pulmonary alveolar epithelial-capillary barrier integrity [204,[206][207][208][209][210][211]. In the respiratory epithelium, LPS EC can modulate α-ENaC expression [212], damage bronchiolar and alveolar epithelial cells [201], stimulate AT1 cells to produce a number of pro-inflammatory mediators [213], and increase expression of a calcium-activated chloride channel (CLCA1) [214].…”

Section: Lps Of E Coli (Lps Ec )mentioning

confidence: 99%

Impact of Bacterial Toxins in the Lungs

Lucas

Hadizamani

Gonzales

et al. 2020

Toxins

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Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung’s innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.

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EphA2 Receptor Signaling Mediates Inflammatory Responses in Lipopolysaccharide-Induced Lung Injury

Cited by 19 publications

References 30 publications

EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis

EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis

Immunomodulatory Functions of Neuronal Guidance Proteins

Impact of Bacterial Toxins in the Lungs

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