Tissue slices in the study of lung metabolism and toxicology.

Freeman, Bruce Α.; O’Neil, John J.

doi:10.1289/ehp.845651

Cited by 25 publications

(6 citation statements)

References 31 publications

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“…A McIlwain tissue chopper (Mickle Laboratory Engineering Co. Ltd., United Kingdom) was used to cut the lungs transversely. The slice thickness was chosen to be 0.7 mm which was predicted by Warburg equation: C 1 = C 0 -A/D*d2/8, where C 1 is the pO 2 in the deepest layer of the slice; C 0 is the pO 2 at the surface of the slice; A is oxygen uptake of the slice in mL/min/mL of tissue; D – diffusion coefficient in mL of oxygen/cm 2 /min; d – slice thickness in cm [33] , [34] . After being cut the slices were placed into a 10 mm dish filled with PBS and washed with agitation.…”

Section: Methodsmentioning

confidence: 99%

Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice

et al. 2011

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BackgroundThe receptor for advanced glycation end-products (RAGE) has been suggested to modulate lung injury in models of acute pulmonary inflammation. To study this further, model systems utilizing wild type and RAGE knockout (KO) mice were used to determine the role of RAGE signaling in lipopolysaccharide (LPS) and E. coli induced acute pulmonary inflammation. The effect of intraperitoneal (i.p.) and intratracheal (i.t.) administration of mouse soluble RAGE on E. coli injury was also investigated.Methodology/Principal FindingsC57BL/6 wild type and RAGE KO mice received an i.t. instillation of LPS, E. coli, or vehicle control. Some groups also received i.p. or i.t. administration of mouse soluble RAGE. After 24 hours, the role of RAGE expression on inflammation was assessed by comparing responses in wild type and RAGE KO. RAGE protein levels decreased in wild type lung homogenates after treatment with either LPS or bacteria. In addition, soluble RAGE and HMGB1 increased in the BALF after E. coli instillation. RAGE KO mice challenged with LPS had the same degree of inflammation as wild type mice. However, when challenged with E. coli, RAGE KO mice had significantly less inflammation when compared to wild type mice. Most cytokine levels were lower in the BALF of RAGE KO mice compared to wild type mice after E. coli injury, while only monocyte chemotactic protein-1, MCP-1, was lower after LPS challenge. Neither i.p. nor i.t. administration of mouse soluble RAGE attenuated the severity of E. coli injury in wild type mice.Conclusions/SignificanceLack of RAGE in the lung does not protect against LPS induced acute pulmonary inflammation, but attenuates injury following live E. coli challenge. These findings suggest that RAGE mediates responses to E. coli-associated pathogen-associated molecular pattern molecules other than LPS or other bacterial specific signaling responses. Soluble RAGE treatment had no effect on inflammation.

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Section: Methodsmentioning

confidence: 99%

Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice

et al. 2011

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“…An intermediate level of complexity that circumvents many of these problems is to work with isolated perfused organs (such as the Langendorrf perfused heart preparation (Chatham and Seymour 2002), everted small intestine (Dixit et al 2012), perfused kidney (Scaduto and Davis 1985), liver and intestinal slices (deGraaf et al 2010) or tissue fragments (Hougardy et al 2008; Kirby et al 2004; Katharina Leithner et al 2014). Perfused organ studies are limited to animal studies, but it is possible to use freshly biopsied or resected human tissues, either as small fragments (Katharina Leithner et al 2014) or as thin slices as originally described by Warburg (Warburg 1923; Berndt 1976; Freeman and Oneil 1984; F. T. Unger et al 2014; Vaira et al 2010; F.T.…”

Section: Preclinical Modelsmentioning

confidence: 99%

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

2016

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Aims In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. Background All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments. Conclusions and Future Work Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials.

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“…This gave rise to the name precision-cut tissue slices. The early extension of the slice technique to lung tissue still produced slices with very variable thickness as a result of the soft and pliable nature of lung tissue [6]. However, a major step towards obtaining lung slices with a more consistent thickness was achieved by inflating the lungs with agarose [7].…”

Section: Lung Slice Preparationmentioning

confidence: 99%

Exploring lung physiology in health and disease with lung slices

Sanderson

2011

Pulmonary Pharmacology & Therapeutics

142

159

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The development of therapeutic approaches to treat lung disease requires an understanding of both the normal and disease physiology of the lung. Although traditional experimental approaches only address either organ or cellular physiology, the use of lung slice preparations provides a unique approach to investigate integrated physiology that links the cellular and organ responses. Living lung slices are robust and can be prepared from a variety of species, including humans, and they retain many aspects of the cellular and structural organization of the lung. Functional portions of intrapulmonary airways, arterioles and veins are present within the alveoli parenchyma. The dynamics of macroscopic changes of contraction and relaxation associated with the airways and vessels are readily observed with conventional low-magnification microscopy. The microscopic changes associated with cellular events, that determine the macroscopic responses, can be observed with confocal or two-photon microscopy. To investigate disease processes, lung slices can either be prepared from animal models of disease or animals exposed to disease invoking conditions. Alternatively, the lung slices themselves can be experimentally manipulated. Because of the ability to observe changes in cell physiology and how these responses manifest themselves at the level of the organ, lung slices have become a standard tool for the investigation of lung disease.

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Tissue slices in the study of lung metabolism and toxicology.

Cited by 25 publications

References 31 publications

Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice

Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

Exploring lung physiology in health and disease with lung slices

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