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Defining the inflammatory signature of human lung explant tissue in the presence and absence of glucocorticoid.

ABSTRACT: BACKGROUND: Airway inflammation is a feature of many respiratory diseases and there is a need for newer, more effective anti-inflammatory compounds. The aim of this study was to develop an ex vivo human lung explant model which can be used to help study the mechanisms underlying inflammatory responses and which can provide a tool to aid drug discovery for inflammatory respiratory diseases such as asthma and COPD. METHOD: Parenchymal lung tissue from 6 individual donors was dissected and cultured with two pro-inflammatory stimuli, lipopolysaccharide (LPS) (1 µg/ml) and interleukin-1 beta (IL-1?) (10 ng/ml) in the presence or absence of dexamethasone (1 µM). Inflammatory responses were assessed using Luminex analysis of tissue culture supernatants to measure levels of 21 chemokines, growth factors and cytokines. RESULTS: A robust and reproducible inflammatory signal was detected across all donors for 12 of the analytes measured following LPS stimulation with a modest fold increase (<2-fold) in levels of CCL22, IL-4, and IL-2; increases of 2-4-fold in levels of CXCL8, VEGF and IL-6 and increases >4-fold in CCL3, CCL4, GM-CSF, IL-10, TNF-? and IL-1?. The inflammatory signal induced by IL-1? stimulation was less than that observed with LPS but resulted in elevated levels of 7 analytes (CXCL8, CCL3, CCL4, GM-CSF, IL-6, IL-10 and TNF-?). The inflammatory responses induced by both stimulations was supressed by dexamethasone for the majority of analytes. CONCLUSIONS: These data provide proof of concept that this ex vivo human lung explant model is responsive to inflammatory signals and could be used to investigate the anti-inflammatory effects of existing and novel compounds. In addition this model could be used to help define the mechanisms and pathways involved in development of inflammatory airway disease. ABBREVIATIONS: COPD: Chronic Obstructive Pulmonary Disease; ICS: inhaled corticosteroids; LPS: lipopolysaccharide; IL-1?: interleukin-1 beta; PSF: penicillin, streptomycin and fungizone.

SUBMITTER: Rimington TL

PROVIDER: S-EPMC5497818 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Defining the inflammatory signature of human lung explant tissue in the presence and absence of glucocorticoid.

Rimington Tracy L TL Hodge Emily E Billington Charlotte K CK Bhaker Sangita S K C Binaya B Kilty Iain I Jelinsky Scott S Hall Ian P IP Sayers Ian I

F1000Research 20170411

<h4>Background</h4> Airway inflammation is a feature of many respiratory diseases and there is a need for newer, more effective anti-inflammatory compounds. The aim of this study was to develop an <i>ex vivo</i> human lung explant model which can be used to help study the mechanisms underlying inflammatory responses and which can provide a tool to aid drug discovery for inflammatory respiratory diseases such as asthma and COPD.<h4>Method</h4> Parenchymal lung tissue from 6 individual donors was ...[more]

PMID: 28721202

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Project description:Migraine is a debilitating condition characterized by recurrent severe head pain. Although mechanisms underlying a migraine attack remain controversial, one proposal is that inflammatory mediator (IM)-induced activation and sensitization of dural afferents contribute to the initiation of migraine pain. We and others have shown that the electrophysiological properties of afferents, both in the absence and the presence of IM, vary as a function of target of innervation. These differences may account for unique aspects of pain syndromes associated with specific body regions. Therefore the purpose of the present study was to test the hypothesis that the electrophysiological properties of dural afferents differ from those innervating the temporalis muscle (TM), a structure in close proximity to the dura but that is not associated with pain syndromes at all similar to migraine. Acutely dissociated retrograde labeled primary afferents innervating the dura and TM were examined with whole cell current-clamp recordings. Passive and active electrophysiological properties were determined before and after the application of IM: (in muM) prostaglandin E(2) (1), bradykinin (10), and histamine (1). In the absence of IM, there were significant differences between the two populations, particularly with respect to the response to suprathreshold stimulation where dural afferents were more excitable than TM afferents. Importantly, although both populations of afferents were sensitized by IM, the pattern of passive and active electrophysiological changes associated with IM-induced sensitization of these two populations of afferents suggested that there were both similarities and marked differences between the two with respect to underlying mechanisms of sensitization. If the differences between dural and TM afferents are due to a differential pattern of ion channel expression rather than differences in the relative density/biophysical properties of the same ion channels, it may be possible to selectively treat migraine pain by targeting the distinct mechanisms underlying IM-induced sensitization of dural afferents.

Dataset Information

Defining the inflammatory signature of human lung explant tissue in the presence and absence of glucocorticoid.

Publications

Defining the inflammatory signature of human lung explant tissue in the presence and absence of glucocorticoid.

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