Imperial College London

DrKieranO'Dea

Faculty of MedicineDepartment of Surgery & Cancer

Senior Lecturer in Translational Critical Care
 
 
 
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k.odea

 
 
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G3.43Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
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99 results found

Tan YY, O'Dea KP, Tsiridou DM, Pac Soo A, Koh MW, Beckett F, Takata Met al., 2022, Circulating Myeloid Cell-derived Extracellular Vesicles as Mediators of Indirect Acute Lung Injury, American Journal of Respiratory Cell and Molecular Biology, ISSN: 1044-1549

Journal article

Baldi RF, Soni S, Patel BV, O'Dea KP, Wilson MR, Takata Met al., 2022, Macrophage-Derived Microvesicles Induce Alveolar Epithelial Cell Death in an In Vitro Stretch Model, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Sachouli E, Tsiridou DM, Takata M, Gordon A, O'Dea KPet al., 2022, Stimulation of Neutrophils in Whole Blood Enhances the Pro-inflammatory Activity of Neutrophil-Derived Microvesicles., FASEB J, Vol: 36 Suppl 1

BACKGROUND: Acute increases in circulating levels of neutrophil-derived microvesicles (N-MVs) during sepsis combined with evidence of enhanced uptake of MVs within the pulmonary microvasculature during endotoxemia in mice, suggests a role for N-MVs in development of indirect acute lung injury (ALI). However, evidence for the pro-inflammatory activity of N-MVs is unclear, with various in vitro studies demonstrating anti-inflammatory effects. Most in vitro investigations of N-MV activity involve stimulation of purified neutrophils with single agonists such as formyl-methionyl-leucyl-phenylalanine (fMLP). This reductionist approach excludes the complex in vivo interplay between different stimuli and other vascular cells contributing to neutrophil responses during sepsis. Here we investigated the proinflammatory activities of N-MVs under more clinically relevant in vitro conditions, treating healthy volunteer whole blood with lipopolysaccharide (LPS) as a sepsis-relevant inflammatory stimulus and fMLP as an acute N-MV inducing stimulus. The activities of N-MVs derived from whole blood as well as isolated neutrophils were evaluated in a monocyte-neutrophil-endothelial cell 'tri-culture' model of pulmonary vascular inflammation. METHODS: N-MVs were generated from whole blood or neutrophils isolated by two-step density gradient centrifugation, by stimulation with fMLP (1 µM, 30 min) alone or combined with LPS pre-treatment (100 ng/ml, 1 h). N-MVs were isolated from blood by anti-CD66b immunomagnetic-bead selection. For the tri-culture assay, isolated neutrophils and immunomagnetic-bead sorted monocytes were cultured with human lung microvascular endothelial cells. N-MVs were incubated in the tri-cultures for 3 h, and MV-induced responses were determined by ELISA and flow cytometric quantification of cell activation markers on monocytes and neutrophils. RESULTS: N-MVs derived from LPS-fMLP-stimulated (but not fMLP-stimulated) whole blood induced significant responses

Journal article

Tsiridou DM, Sachouli E, Takata M, O'Dea KPet al., 2022, Neutrophil-Derived Microvesicles Enhance Pulmonary Vascular Inflammation via a Toll-like Receptor 4 Signaling-Dependent Mechanism., FASEB J, Vol: 36 Suppl 1

BACKGROUND: Circulating neutrophil-derived microvesicles (NMVs) are markedly elevated during sepsis and therefore could have a role in the development of indirect acute lung injury (ALI). We recently found that NMV-enriched CD11b+ MVs, immunoaffinity isolated from lipopolysaccharide (LPS)-stimulated healthy volunteer blood, have potent pro-inflammatory activity in a human peripheral blood mononuclear cell (PBMC) and lung microvascular endothelial cell (HLMEC) coculture model of pulmonary vascular inflammation (1). By contrast, immunoaffinity isolated platelet-MVs (CD61+ ) produced negligible responses in these assays, suggesting specificity of the NMV-enriched CD11b+ MV, activity. Here, we investigated the signaling mechanisms responsible for NMV-mediated activation of monocytes and HLMECs in this model. METHODS: Heparinized blood from healthy donors was treated with LPS (100 ng/ml, 3 h) and NMVs (CD66b+ ) were isolated by positive immunoaffinity selection. NMVs were then incubated in PBMC-HLMEC cocultures for 4 h. NMV-induced responses were determined by flow cytometric quantification of cell surface activation markers (ICAM-1 for HLMECs, ICAM-1 and tissue factor for monocytes) and pro-inflammatory cytokine release by ELISA (TNFα, IL-8, IL-6, MCP-1). RESULTS: NMV-induced HLMEC activation required the presence of monocytes and was completely attenuated by anti-TNFα neutralizing antibody (ICAM-1: isotype control 302±103 vs anti-TNFα 66±29; p<0.01). Pharmacological inhibition of mitogen-activated protein kinases p38, MEK1-MEK2 and phosphoinositide-3 kinase ablated monocyte and HLMEC activation. Monocyte activation was prevented in the presence of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 (e.g., TNFα release: vehicle 1108±257 vs TAK-242 16±12; p<0.001) and partially inhibited by an anti-TLR4 neutralizing antibody. However, the LPS inhibitor polymyxin-B had no effect on these responses, indicating that LP

Journal article

Soni S, O'Dea K, Abe E, Khamdan M, Shah S, Sarathchandra P, Wilson MR, Takata Met al., 2022, Microvesicle-mediated communication within the alveolar space: mechanisms of uptake by epithelial cells and alveolar macrophages, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224

Intra-alveolar microvesicles (MVs) are important mediators of inter-cellular communication within the alveolar space, and are key components in the pathophysiology of lung inflammation such as acute respiratory distress syndrome (ARDS). Despite the abundance of data detailing the pro-inflammatory effects of MVs, it remains unclear how MVs interact or signal with target cells in the alveolus. Using both in vivo and in vitro alveolar models, we analyzed the dynamics of MV uptake by resident alveolar cells: alveolar macrophages and epithelial cells. Under resting conditions, the overwhelming majority of MVs were taken up by alveolar macrophages. However, following lipopolysaccharide (LPS)-mediated inflammation, epithelial cells internalized significantly more MVs (p<0.01) whilst alveolar macrophage internalization was significantly reduced (p<0.01). We found that alveolar macrophages adopted a pro-inflammatory phenotype after internalizing MVs under resting conditions, but reduction of MV uptake following LPS pre-treatment was associated with loss of inflammatory phenotype. Instead, MVs induced significant epithelial cell inflammation following LPS pre-treatment, when MV internalization was most significant. Using pharmacological inhibitors, we interrogated the mechanisms of MV internalization to identify which endocytic pathways and cell surface receptors are involved. We demonstrated that epithelial cells are exclusively dependent on the clathrin and caveolin dependent endocytotic pathway, whereas alveolar macrophage uptake may involve a significant phagocytic component. Furthermore, alveolar macrophages predominantly engulf MVs via scavenger receptors whilst, epithelial cells internalize MVs via a phosphatidylserine/integrin receptor mediated pathway (specifically alpha V beta III), which can be inhibited with phosphatidylserine-binding protein (i.e. annexin V). In summary, we have undertaken a comprehensive evaluation of MV internalization within the alveolar

Journal article

Tan YY, O'Dea KP, Patel BV, Takata Met al., 2022, Investigation of microvesicle uptake by mouse lung-marginated monocytes in vitro., Bio-protocol, Vol: 12, Pages: 1-1, ISSN: 2331-8325

Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com.

Journal article

Koh MW, Baldi RF, Soni S, Handslip R, Tan YY, O'Dea KP, Malesevic M, McAuley DF, O'Kane CM, Patel BV, Takata M, Wilson MRet al., 2021, Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 421-430, ISSN: 1073-449X

RATIONALE: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection. OBJECTIVES: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury. METHODS: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage. CONCLUSIONS: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.

Journal article

Baldi RF, Soni S, Patel BV, O'Dea KP, Wilson MR, Takata Met al., 2021, Microvesicle-Mediated Enhancement of TNF-Driven Apoptosis During VILI, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Soni S, Garner J, O'Dea K, Kohn M, Finney L, Tirlapur N, Srikanthan K, aboelhassan A, Singh S, Wilson M, Wedzicha J, Kemp S, Usmani O, Shah P, Takata Met al., 2021, Intra-alveolar neutrophil-derived microvesicles are associated with disease severity in COPD, American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol: 320, Pages: L73-L83, ISSN: 1040-0605

Despite advances in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD but their association to COPD disease severity remains unknown. We analysed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from sixty-two patients with mild to very severe COPD (51% male; mean age: 65.9 years). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, exercise testing) and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF (leukocyte, PMN (polymorphonuclear leukocyte i.e. neutrophil), monocyte, epithelial and platelet MVs) and plasma (leukocyte, PMN, monocyte and endothelial MVs), and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including FEV1, mMRC dyspnoea score, 6-minute walk test, hyperinflation and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically-relevant disease severity indices. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome.

Journal article

Tsiridou DM, O'Dea KP, Tan YY, Takata Met al., 2020, Late Breaking Abstract - Myeloid-derived microvesicles as acute mediators of sepsis-induced lung vascular inflammation, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Tsiridou D, O'Dea K, Tan Y, Takata Met al., 2020, Neutrophil-Derived Microvesicle Uptake under Flow Conditions in an I<it>n Vitro</it> Model of Pulmonary Vascular Inflammation, Annual Meeting on Experimental Biology, Publisher: WILEY, ISSN: 0892-6638

Conference paper

Hua R, Edey LF, O'Dea KP, Howe L, Herbert BR, Cheng W, Zheng X, MacIntyre DA, Bennett PR, Takata M, Johnson MRet al., 2020, CCR2 mediates the adverse effects of LPS in the pregnant mouse, Biology of Reproduction, Vol: 102, Pages: 445-455, ISSN: 0006-3363

In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.

Journal article

Zöllner J, Howe LG, Edey LF, O'Dea KP, Takata M, Leiper J, Johnson MRet al., 2020, LPS-induced hypotension in pregnancy: the effect of progesterone supplementation, Shock, Vol: 53, Pages: 199-207, ISSN: 1073-2322

Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS.Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10 mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10 μg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours.Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar.This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.

Journal article

O'Dea KP, Tan YY, Shah S, Patel B, Tatham KC, Wilson MR, Soni S, Takata Met al., 2020, Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 9

Journal article

Tan YY, O'Dea KP, Takata M, 2020, Circulating Neutrophil-Derived Microvesicles During Endotoxaemia Induce Pulmonary Vascular Injury, Virtual International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Oakley C, Koh M, Baldi R, Soni S, O'Dea K, Takata M, Wilson Met al., 2019, Ventilation following established ARDS: a preclinical model framework to improve predictive power, Thorax, Vol: 74, Pages: 1120-1129, ISSN: 1468-3296

Background Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of β-agonist treatment, which is effective in simple models but not clinically.Methods Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI).Results Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable.Conclusions We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.

Journal article

Soni S, Tirlapur N, O'Dea KP, Takata M, Wilson MRet al., 2019, Microvesicles as new therapeutic targets for the treatment of the acute respiratory distress syndrome (ARDS), EXPERT OPINION ON THERAPEUTIC TARGETS, Vol: 23, Pages: 931-941, ISSN: 1472-8222

Journal article

Soni S, O'Dea K, Tan YY, Cho K, Abe E, Romano R, Cui J, Ma D, Sarathchandra P, Wilson MR, Takata Met al., 2019, ATP redirects cytokine trafficking and promotes novel membrane TNF signalling via microvesicles, FASEB Journal, ISSN: 0892-6638

Cellular stress or injury induces release of endogenous danger signals such as ATP, which plays a central role in activating immune cells. ATP is essential for the release of nonclassically secreted cytokines such as IL-1β but, paradoxically, has been reported to inhibit the release of classically secreted cytokines such as TNF. Here, we reveal that ATP does switch off soluble TNF (17 kDa) release from LPS-treated macrophages, but rather than inhibiting the entire TNF secretion, ATP packages membrane TNF (26 kDa) within microvesicles (MVs). Secretion of membrane TNF within MVs bypasses the conventional endoplasmic reticulum– and Golgi transport–dependent pathway and is mediated by acid sphingomyelinase. These membrane TNF–carrying MVs are biologically more potent than soluble TNF in vivo, producing significant lung inflammation in mice. Thus, ATP critically alters TNF trafficking and secretion from macrophages, inducing novel unconventional membrane TNF signaling via MVs without direct cell-to-cell contact. These data have crucial implications for this key cytokine, particularly when therapeutically targeting TNF in acute inflammatory diseases.—Soni, S., O’Dea, K. P., Tan, Y. Y., Cho, K., Abe, E., Romano, R., Cui, J., Ma, D., Sarathchandra, P., Wilson, M. R., Takata, M. ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles.

Journal article

Matsumoto S, Iki Y, Abe M, O'Dea KP, Shigemitsu H, Takata M, Wakabayashi Ket al., 2019, Neutrophil-Derived Microvesicles as a Novel Biomarker in Hyperoxic Bronchopulmonary Dysplasia in Mice, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Tan YY, O'Dea KP, Soo AP, Takata Met al., 2019, Investigation into the Roles of Circulating Microvesicles Within the Pulmonary Vasculature Using Ex Vivo Isolated Perfused Lung, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Gordon AC, Santhakumaran S, Al-Beidh F, Orme RML, Perkins GD, Singer M, McAuley DF, Mason AJ, Ward JK, ODea KP, Felton T, Cross M, Best-Lane J, Lexow J, Campbell A, Ashby Det al., 2018, Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT, Efficacy and Mechanism Evaluation, Vol: 5, Pages: 1-124, ISSN: 2050-4365

Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial

Journal article

Antcliffe D, Ward J, Marshall T, Al-Beidh F, O'Dea K, Gordon Aet al., 2018, Multivariate analysis of cytokines in septic shock predicts outcome, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X

Conference paper

Antcliffe D, Wolfer A, O'Dea K, Takata M, Holmes E, Gordon ACet al., 2018, Profiling inflammatory markers in patients with pneumonia on intensive care, Scientific Reports, Vol: 8, ISSN: 2045-2322

Clinical investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for a panel of inflammatory mediators to aid in the diagnosis. Forty-four ventilated patients, 17 with pneumonia and 27 with brain injuries, eight of whom developed VAP, were recruited. 51 inflammatory mediators, including cytokines and oxylipins, were measured in patients’ serum using flow cytometry and mass spectrometry. The mediators could separate patients admitted to ICU with pneumonia compared to brain injury with an area under the receiver operating characteristic curve (AUROC) 0.75 (0.61–0.90). Changes in inflammatory mediators were similar in both groups over the course of ICU stay with 5,6-dihydroxyeicosatrienoic and 8,9-dihydroxyeicosatrienoic acids increasing over time and interleukin-6 decreasing. However, brain injured patients who developed VAP maintained inflammatory profiles similar to those at admission. A multivariate model containing 5,6-dihydroxyeicosatrienoic acid, 8,9-dihydroxyeicosatrienoic acid, intercellular adhesion molecule-1, interleukin-6, and interleukin-8, could differentiate patients with VAP from brain injured patients without infection (AUROC 0.94 (0.80–1.00)). The use of a selected group of markers showed promise to aid the diagnosis of VAP especially when combined with clinical data.

Journal article

Tatham KC, O'Dea KP, Romano R, Donaldson HE, Wakabayashi K, Patel BV, Thakuria L, Simon AR, Sarathchandra P, POPSTAR Investigators, Marczin N, Takata Met al., 2018, Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury, Thorax, Vol: 73, Pages: 350-360, ISSN: 1468-3296

Rationale Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.Objective To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.Methods Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.Results In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.Conclusions These results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.

Journal article

Edey LF, Georgiou H, O'Dea KP, Mesiano S, Herbert BR, Lei K, Hua R, Markovic D, Waddington SN, MacIntyre D, Bennett P, Takata M, Johnson MRet al., 2017, Progesterone, the maternal immune system and the onset of parturition in the mouse, Biology of Reproduction, Vol: 98, Pages: 376-395, ISSN: 1529-7268

The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2) and the onset of parturition was examined in: 1) naïve mice delivering at term; 2) E16 mice treated with RU486 (P4-antagonist) to induce preterm parturition; and 3) in mice treated with P4 to prevent term parturition.In naïve mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43 and COX-2 increased with, but not before, parturition.With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9h post RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition.In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation, myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased.These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabour factor synthesis via mRNA dependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation.

Journal article

Wilson MR, Petrie JE, Shaw MW, Hu C, Oakley CM, Woods SJ, Patel BV, O'Dea KP, Takata Met al., 2017, High fat feeding protects mice from ventilator-induced lung injury, via neutrophil-independent mechanisms, Critical Care Medicine, Vol: 45, Pages: e831-e839, ISSN: 1530-0293

Objective: Obesity has a complex impact on acute respiratory distress syndrome patients, being associated with increased likelihood of developing the syndrome but reduced likelihood of dying. We propose that such observations are potentially explained by a model in which obesity influences the iatrogenic injury that occurs subsequent to intensive care admission. This study therefore investigated whether fat feeding protected mice from ventilator-induced lung injury.Design: In vivo study.Setting: University research laboratory.Subjects: Wild-type C57Bl/6 mice or tumor necrosis factor receptor 2 knockout mice, either fed a high-fat diet for 12–14 weeks, or age-matched lean controls.Interventions: Anesthetized mice were ventilated with injurious high tidal volume ventilation for periods up to 180 minutes.Measurements and Main Results: Fat-fed mice showed clear attenuation of ventilator-induced lung injury in terms of respiratory mechanics, blood gases, and pulmonary edema. Leukocyte recruitment and activation within the lungs were not significantly attenuated nor were a host of circulating or intra-alveolar inflammatory cytokines. However, intra-alveolar matrix metalloproteinase activity and levels of the matrix metalloproteinase cleavage product soluble receptor for advanced glycation end products were significantly attenuated in fat-fed mice. This was associated with reduced stretch-induced CD147 expression on lung epithelial cells.Conclusions: Consumption of a high-fat diet protects mice from ventilator-induced lung injury in a manner independent of neutrophil recruitment, which we postulate instead arises through blunted up-regulation of CD147 expression and subsequent activation of intra-alveolar matrix metalloproteinases. These findings may open avenues for therapeutic manipulation in acute respiratory distress syndrome and could have implications for understanding the pathogenesis of lung disease in obese patients.

Journal article

Zöllner J, Howe LG, Edey LF, O'Dea KP, Takata M, Gordon F, Leiper J, Johnson MRet al., 2017, The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice., Biology of Reproduction, Vol: 97, Pages: 258-272, ISSN: 1529-7268

Sepsis is the leading cause of direct maternal mortality, but there are no data directly comparing the response to sepsis in pregnant and nonpregnant (NP) individuals. This study uses a mouse model of sepsis to test the hypothesis that the cardiovascular response to sepsis is more marked during pregnancy. Female CD1 mice had radiotelemetry probes implanted and were time mated. NP and day 16 pregnant CD-1 mice received intraperitoneal lipopolysaccharide (LPS; 10 μg, serotype 0111: B4). In a separate study, tissue and serum (for RNA, protein and flow cytometry studies), aorta and uterine vessels (for wire myography) were collected after LPS or vehicle control administration. Administration of LPS resulted in a greater fall in blood pressure in pregnant mice compared to NP mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors, and circulating leukocytes, but with a greater monocyte and lesser neutrophil margination in the lungs of pregnant mice. Baseline markers of cardiac dysfunction and apoptosis as well as cytokine expression were higher in pregnant mice, but the response to LPS was similar in both groups as was the ex vivo assessment of vascular function. In pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response. We conclude that endotoxemia induces a more marked hypotensive response in pregnant compared to NP mice. These changes were not associated with a more marked systemic inflammatory response in pregnant mice, although monocyte lung margination was greater. The more marked hypotensive response to LPS may explain the greater vulnerability to some infections exhibited by pregnant women.

Journal article

Tan YY, O'Dea KP, Soni S, Shah S, Patel BV, Takata Met al., 2017, Enhanced Recognition and Internalisation of Microvesicles by Lung-Marginated, Ly-6C(high) Monocytes During Endotoxaemia, Annual Meeting of the American-Society-for-Pharmacology-and-Experimental-Therapeutics (ASPET) at Experimental Biology Meeting, Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638

Conference paper

Davies R, O'Dea KP, Soni S, Ward JK, O'Callaghan DJP, Takata M, Gordon ACet al., 2017, P362: Vasopressin alone and with noradrenaline attenuates TNF-α production in an in-vitro model of monocyte priming and deactivation, 37th International Symposium on Intensive Care and Emergency Medicine, Publisher: BioMed Central, ISSN: 1364-8535

Conference paper

Wilson MR, Wakabayashi K, Bertok S, Oakley C, Patel BV, O'Dea KP, Cordy JC, Morley PJ, Bayliffe AI, Takata Met al., 2017, Inhibition of TNF receptor p55 by a domain antibody attenuates the initial phase of acid-induced lung injury in mice, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development ofacute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has beenhampered by its complex biology. TNF signals through two receptors, p55 and p75, whichplay differential roles in pulmonary edema formation during ARDS. We have recentlyshown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator36induced lung injury. In the current study we explored the efficacy of this antibody in mousemodels of acid-induced lung injury, to investigate the longer consequences of treatment.Methods: We employed two acid-induced injury models, an acute ventilated model and aresolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally orintranasally with p55-targeting dAb or non-targeting ‘dummy’ dAb, 1 or 4 hours before acidinstillation.Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratorysystem elastance, pulmonary inflammation and edema in both the ventilated and resolvingmodels. Pretreatment with p55-targeting dAb significantly attenuated physiological markersof ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in theventilated model, with signs that altered cytokine production and leukocyte recruitmentpersisted beyond the very acute phase.Conclusions: These results demonstrate that the p55-targeting dAb attenuates lung injury andedema formation in models of ARDS induced by acid aspiration, with protection from asingle dose lasting up to 24 hours. Together with our previous data, the current study lends support towards the clinical targeting of p55 for patients with, or at risk of ARDS.

Journal article

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