The Intrinsic Apoptotic Pathway Is Required for Lipopolysaccharide-Induced Lung Endothelial Cell Death

Wang, Helena L.; Akıncı, İbrahim Özkan; Baker, Christina M.; Urich, Daniela; Bellmeyer, Amy; Jain, Manu; Chandel, Navdeep S.; Mutlu, Gökhan M.; Budinger, G. R. Scott

doi:10.4049/jimmunol.179.3.1834

Cited by 55 publications

(40 citation statements)

References 39 publications

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“…7,22 However, it was also shown that exposure to LPS could directly cause tissue damage by triggering apoptotic cell death in bronchial epithelial 23 and endothelial 24 cells. In addition, LPS was reported to induce apoptosis in human alveolar macrophages in a dosedependent manner.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

Temann

Golovina

Neuhaus

et al. 2016

Human Vaccines & Immunotherapeutics

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The development of systems that are more accurate and time-efficient in predicting safety and efficacy of target products in humans are critically important in reducing the cost and duration of pharmaceutical development. To circumvent some of the limitations imposed by the use of animal models, ex vivo systems, such as precision-cut lung slices (PCLS), have been proposed as an alternative for evaluating safety, immunogenicity and efficacy of vaccines and pharmaceuticals. In this study, we have established a human PCLS system and methodology for PCLS cultivation that can provide long-term viability and functionality in culture. Using these techniques, we found that cultured PCLS remained viable for at least 14 d in culture and maintained normal metabolic activity, tissue homeostasis and structural integrity. To investigate whether cultured PCLS remained functional, lipopolysaccharide (LPS) was used as a target stimulating compound. We observed that after an 18-hour incubation with LPS, cultured PCLS produced a set of pro-inflammatory cytokines, including TNF-a, IL-1b, IL-6 and IL-10 as well as the enzyme COX-2. Furthermore, cultured PCLS were shown to be capable of generating re-call immune responses, characterized by cytokine production, against antigens commonly found in routine vaccinations against influenza virus and tetanus toxoid. Taken together, these results suggest that human PCLS have the potential to be used as an alternative, high-throughput, ex vivo system for evaluating the safety, and potentially immunogenicity, of vaccines and pharmaceuticals.

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Section: Discussionmentioning

confidence: 99%

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

Temann

Golovina

Neuhaus

et al. 2016

Human Vaccines & Immunotherapeutics

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“…The cellular injury induced by LPS appears to be related to apoptosis, in contrast to the oleic acid model, in which the injury is due to a direct toxic effect resulting in necrosis. Apoptosis of endothelial cells develops rapidly following administration of LPS and precedes other tissue damage (72,230). Systemic treatment with the broad-spectrum caspase inhibitor Z-VAD.fmk blocks apoptosis and improves survival in mice treated with intravenous LPS (111).…”

Section: Models That Target Primarily the Capillary Endotheliummentioning

confidence: 99%

Animal models of acute lung injury

Matute-Bello

Frevert

Martin

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

1,415

1,397

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Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.

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“…LPS Administration and Collection of Bronchoalveolar Lavage Fluid (BAL)-Mice were treated with a single intraperitoneal injection of PBS or LPS (6 mg/kg in 50 l of PBS) as described (20). Lung proteins were obtained by homogenizing lung tissue collected from the peripheral 1-2 mm of each lobe as previously described (21,22).…”

Section: Methodsmentioning

confidence: 99%

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

Lubarski-Gotliv

Asher

Dada

et al. 2016

Journal of Biological Chemistry

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The FXYD proteins are a family of small membrane proteins that share an invariant four amino acid signature motif F-X-Y-D and act as tissue-specific regulatory subunits of the Na,KATPase. FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max . However, unlike other family members FXYD5 appears to have additional functions, which cannot be readily explained by modulation of transport kinetics. Knockdown of FXYD5 in MDA-MB-231 breast cancer cells largely decreases expression and secretion of the chemokine CCL2 (MCP-1). A related effect has also been observed in renal cell carcinoma cells. The current study aims to further characterize the relationship between the expression of FXYD5 and CCL2 secretion. We demonstrate that transfection of M1 epithelial cell line with FXYD5 largely increases lipopolysaccharide (LPS) stimulated CCL2 mRNA and secretion of the translated protein. We have completed a detailed analysis of the molecular events leading to the above response. Our key findings indicate that FXYD5 generates a late response by increasing the surface expression of the TNF␣ receptor, without affecting its total protein level, or mRNA transcription. LPS administration to mice demonstrates induced secretion of CCL2 and TNF␣ in FXYD5-expressing lung peripheral tissue, which suggests a possible role for FXYD5 in normal epithelia during inflammation.FXYD is a family of type I plasma membrane proteins characterized by the extracellular motif Phe-Xxx-Tyr-Asp. All seven mammalian members of this family specifically interact with the Na,K-ATPase and they have been described to act as tissue specific regulators or auxiliary subunits of the Na,KATPase whose role is to adjust the pump's activity to the cell environment (1). FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max (2, 3). However, in addition to regulating Na,K-ATPase kinetics, FXYD5 appears to have other functions. FXYD5 has been identified as a cancer-associated protein whose expression inhibits E-cadherin and promotes metastasis (4). Clinical studies have demonstrated correlations between the abundance of FXYD5 and the progression of malignancies and survival chances of patients with various human cancers (for review see Ref. 5). Silencing FXYD5 decreases individual and collective cell motility, while its overexpression has the opposite effect (6 -8). In addition, the expression of FXYD5 has been associated with changes in cytoskeletal organization, altered cell shape and impairment of tight and adherence junctions (6 -10). The above observations are consistent with the fact that the extracellular domain of FXYD5 is much longer than that of other FXYD proteins and presumably undergoes excessive O-glycosylation (4, 11).Prev...

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The Intrinsic Apoptotic Pathway Is Required for Lipopolysaccharide-Induced Lung Endothelial Cell Death

Cited by 55 publications

References 39 publications

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices

Animal models of acute lung injury

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

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