Imperial College London

DrMichaelWilson

Faculty of MedicineDepartment of Surgery & Cancer

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3315 8292michael.wilson

 
 
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Location

 

G.3.43Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
Year
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78 results found

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, 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, 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

Wilson M, Takata M, 2019, Mechanical Ventilation in Mice: Does Longer Equal Better?, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 60, Pages: 137-138, ISSN: 1044-1549

Journal article

Koh MW, Takata M, Wilson MR, 2019, Cyclophilin A as a Novel Mediator in Acute Lung Injury, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Garner J, Soni S, O'Dea K, Srikanthan K, Tenda E, Aboelhassan A, Singh S, Kemp SV, Wilson MR, Usmani OS, Shah PL, Takata Met al., 2018, Late Breaking Abstract - Intra-alveolar neutrophil-derived microvesicles: a biomarker of COPD severity, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Du W, Takata M, Wilson MR, 2018, Activation of lung-marginated monocytes in initiating ventilator-induced extra-pulmonary inflammation, British-Journal-of-Anaesthesia (BJA) Research Forum, Publisher: ELSEVIER SCI LTD, Pages: E25-E26, ISSN: 0007-0912

Conference paper

Nakamura H, Wilson MR, Yao K, Mumby S, Adcock IM, Takata M, Patel BVet al., Modulation Of Mechanical Ventilation-Induced Alveolar Epithelial Cell Death Signaling By Underlying Lung Inflammation, American Thoracic Society 2018, Publisher: American Thoracic Society

Conference paper

Soni S, Wilson MR, Dea KPO, Tan YY, Abe E, Takata Met al., 2018, Microvesicles Mediate Long-Range Membrane TNF Signalling, Inducing Inflammatory Changes Consistent with Acute Lung Injury, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Oakley CM, Wilson M, O'Dea K, Cordy J, Takata Met al., 2017, Tnfr1 Inhibition Mitigates Susceptibility To Ventilator-Induced Lung Injury In Mice With Established Ards, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X

Conference paper

Tirlapur N, O'Dea K, Soni S, Davies R, Sooranna S, Johnson M, Wilson M, Takata Met al., 2017, Pathological Stretch Of Endothelial Cells Activates Marginated Monocytes To Release Microvesicles In An In Vitro Model Of Ventilator-Induced Lung Injury, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

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 (VILI). Design: In vivo study.Setting: University research laboratory.Subjects: Wildtype C57Bl/6 mice or TNF 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 VILI 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 (MMP) activity and levels of the MMP cleavage product sRAGE 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 VILI in a manner independent of neutrophil recruitment, which we postulate instead arises through blunted upregulation of CD147 expression and subsequent activation of intra-alveolar MMPs. These findings may open avenues for therapeutic manipulation in ARDS, and could have implications for understanding the pathogenesis of lung disease in obese patients.

Journal article

Takata M, Wilson MR, 2017, If We Ask a Mouse about Biotrauma, Will It Give Us a Sensible Answer?, ANESTHESIOLOGY, Vol: 126, Pages: 766-767, ISSN: 0003-3022

Journal article

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

Takata M, Wilson M, Editorial View: If we ask a mouse about biotrauma, will it give us a sensibleanswer?, Anesthesiology, ISSN: 1528-1175

Acuterespiratory distress syndrome (ARDS) is a major cause of mortalityin critical care, but to date no specific treatment exists.There is growing concern about our failure to translate from bench to bedside within the acute lung injury research community, and the crucial importance of better modelling in preclinical studiesto identify targetswithmore predictivepoweris increasingly appreciated. Mechanical ventilation, while being a vital tool forsupport of ARDSpatients, produces or worsens lung injury. This ‘ventilator-­induced lung injury’(VILI)hassubstantive negative impact on theoutcomeof ARDS.Increasing tidal volumes are associated with enhanced releaseof local and systemic inflammatory mediatorsinpatients, andanimal models demonstrated that excessive tidal volumes inducelung inflammation,edema and physiological dysfunction. Such findings have lent support to the ‘biotrauma’ hypothesis, i.e. VILIpromotes the release of inflammatorymediators,which play a criticalrole in the progression of injury of the lungs as well asother systemic organs [1].In this issueof Anesthesiology, Lex and Uhlig [2] investigatewhether this biotraumacan be studied in so-­called ‘one-­hit’ models of VILI in mice. Their resultsprovide useful information for physiologists to better design mouse VILI experiments, but more importantly, provoke a series of important questionsthat areessentialfor cliniciansdesiring to interpret animal VILI models for future clinical translation.

Journal article

Wilson MR, Takata M, John AE, Habgood A, Porte J, Tatler AL, Stavrou A, Miele G, Jolly L, Knox AJ, Offermanns S, Jenkins RGet al., 2016, Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33–mediated macrophage polarization and emphysema, Science Signaling, Vol: 9, ISSN: 1945-0877

Heterotrimeric guanine nucleotide–binding protein (G protein) signaling links hundreds of Gprotein–coupled receptors (GPCRs) with four G protein signaling pathways. Two of these,one mediated by Gq and G11 (Gq/11) and the other by G12 and G13 (G12/13), are implicated inthe force-dependent activation of transforming growth factor–β (TGFβ) in lung epithelialcells. Reduced TGFβ activation in alveolar cells leads to emphysema, whereas enhancedTGFβ activation promotes acute lung injury and idiopathic pulmonary fibrosis. Therefore,precise control of alveolar TGFβ activation is essential for alveolar homeostasis. Here, weinvestigated the involvement of the Gq/11and G12/13 pathways in epithelial cells in generatingactive TGFβ and regulating alveolar inflammation. Mice deficient in both Gαq and Gα11developed inflammation that was primarily caused by alternatively activated (M2-polarized)macrophages, enhanced matrix metalloprotease 12 (MMP12) production, and age-relatedalveolar airspace enlargement consistent with emphysema. Mice with impaired Gq/11signaling had reduced stretch-mediated generation of TGFβ by epithelial cells and enhancedmacrophage MMP12 synthesis, but were protected from the effects of ventilator-induced lunginjury. Furthermore, synthesis of the cytokine interleukin-33 (IL-33) was increased in thesealveolar epithelial cells, resulting in the M2-type polarization of alveolar macrophages independently of the effect on TGFβ. Our results suggest that alveolar Gq/11 signalingmaintains alveolar homeostasis, and likely independently increases TGFβ activation inresponse to mechanical stress of the epithelium and decreases epithelial IL-33 synthesis.Together, these findings suggest that disruption of Gq/11 signaling promotes inflammatoryemphysema but protects against mechanically induced lung injury.

Journal article

Takata M, Soni S, Wilson MR, O'Dea KP, Yoshida M, Katbeh U, Woods Set al., 2016, Alveolar macrophage-derived microvesicles mediate acute lung injury, Thorax, Vol: 71, Pages: 1020-1029, ISSN: 1468-3296

Background Microvesicles (MVs) are important mediators of intercellular communication, packaging a variety of molecular cargo. They have been implicated in the pathophysiology of various inflammatory diseases; yet, their role in acute lung injury (ALI) remains unknown.Objectives We aimed to identify the biological activity and functional role of intra-alveolar MVs in ALI.Methods Lipopolysaccharide (LPS) was instilled intratracheally into C57BL/6 mice, and MV populations in bronchoalveolar lavage fluid (BALF) were evaluated. BALF MVs were isolated 1 hour post LPS, assessed for cytokine content and incubated with murine lung epithelial (MLE-12) cells. In separate experiments, primary alveolar macrophage-derived MVs were incubated with MLE-12 cells or instilled intratracheally into mice.Results Alveolar macrophages and epithelial cells rapidly released MVs into the alveoli following LPS. At 1 hour, the dominant population was alveolar macrophage-derived, and these MVs carried substantive amounts of tumour necrosis factor (TNF) but minimal amounts of IL-1β/IL-6. Incubation of these mixed MVs with MLE-12 cells induced epithelial intercellular adhesion molecule-1 (ICAM-1) expression and keratinocyte-derived cytokine release compared with MVs from untreated mice (p<0.001). MVs released in vitro from LPS-primed alveolar macrophages caused similar increases in MLE-12 ICAM-1 expression, which was mediated by TNF. When instilled intratracheally into mice, these MVs induced increases in BALF neutrophils, protein and epithelial cell ICAM-1 expression (p<0.05).Conclusions We demonstrate, for the first time, the sequential production of MVs from different intra-alveolar precursor cells during the early phase of ALI. Our findings suggest that alveolar macrophage-derived MVs, which carry biologically active TNF, may play an important role in initiating ALI.

Journal article

Halford P, Woods S, Wilson M, Takata Met al., 2016, Murine pulmonary cell response to varying degrees of mechanical ventilation and its modification by lipopolysaccharide, Meeting of the Difficult-Airway-Society, Publisher: Oxford University Press (OUP), Pages: E933-E934, ISSN: 1471-6771

Conference paper

Wilson M, Petrie J, Shaw M, Oakley C, Patel BV, O'Dea KP, Takata Met al., 2016, High Fat Feeding Protects Mice From Ventilator-Induced Lung Injury Via A Neutrophil-Independent Mechanism, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Soni S, Yoshida M, Woods S, O'Dea K, Wilson M, Takata Met al., 2015, Microvesicles derived from alveolar macrophages mediate epithelial activation via a TNF dependant mechanism, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Patel BV, Tatham KC, Wilson MR, O'Dea KP, Takata Met al., 2015, In vivo compartmental analysis of leukocytes in mouse lungs, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 309, Pages: L639-L652, ISSN: 1522-1504

The lung has a unique structure consisting of three functionally different compartments (alveolar, interstitial, and vascular) situated in an extreme proximity. Current methods to localize lung leukocytes using bronchoalveolar lavage and/or lung perfusion have significant limitations for determination of location and phenotype of leukocytes. Here we present a novel method using in vivo antibody labelling to enable accurate compartmental localization/quantification and phenotyping of mouse lung leukocytes. Anesthetized C57BL/6 mice received combined in vivo intravenous and intratracheal labelling with fluorophore-conjugated anti-CD45 antibodies, and lung single cell suspensions were analyzed by flow cytometry. The combined in vivo intravenous and intratracheal CD45 labelling enabled robust separation of the alveolar, interstitial, and vascular compartments of the lung. In naive mice, the alveolar compartment consisted predominantly of resident alveolar macrophages. The interstitial compartment, gated by events negative for both intratracheal and intravenous CD45 staining, showed two conventional dendritic cell populations, as well as a Ly6C(lo) monocyte population. Expression levels of MHCII on these interstitial monocytes were much higher than the vascular Ly6C(lo) monocyte populations. In mice exposed to acid-aspiration induced lung injury, this protocol also clearly distinguished the three lung compartments showing the dynamic trafficking of neutrophils and exudative monocytes across the lung compartments during inflammation and resolution. This simple in vivo dual labelling technique substantially increases the accuracy and depth of lung flow cytometric analysis, facilitates a more comprehensive examination of lung leukocyte pools, and enables the investigation of previously poorly defined 'interstitial' leukocyte populations during models of inflammatory lung diseases.

Journal article

Patel BV, Tatham KC, Wilson MR, O'Dea K, Takata Met al., 2015, In Vivo Compartmental Labeling of the Mouse Lung, American Thoracic Society, Publisher: ATS Journals, Pages: A3926-A3926, ISSN: 1073-449X

ShareModerators: G.N. Maksym, PhD, R.S. Harris, MD, J.C. Sieren, PhDSession Info: Mini Symposium, [C18] STATE OF PLAY IN RESPIRATORY STRUCTURE AND FUNCTION: SEEING IS BELIEVINGDay/Date: Tuesday, May 19, 2015Session Time: 9:30 AM - 11:30 AMRoom: Mile High Ballroom 2C/3C (Lower Level)Location: Colorado Convention CenterIn Vivo Compartmental Labeling of the Mouse Lung, [Publication Page: A3926]B.V. Patel, MBBS MRCP FRCA PhD, K.C. Tatham, MBBS, M.R. Wilson, PhD, K.P. O'Dea, PhD, M. Takata, MDLondon/UKRationaleCurrent methods for compartmental analyses of lungs using bronchoalveolar lavage (BAL) and/or lung perfusion have significant limitations for accurate determination of location and phenotype of lung leukocytes. BAL retrieves only <25% of intra-alveolar cells (1) and lung perfusion fails to remove vascular marginated cell populations (2). We present a novel method of in vivo antibody labelling to facilitate the accurate compartmental investigation of mouse lung leukocytes by flow cytometry.MethodsAnesthetized C57BL6 mice underwent tracheostomy and venous cannulation. An anti-CD45 antibody (PE-conjugated) was injected intravenously and allowed to circulate for 5 minutes. Mice were then exsanguinated and lungs immediately flooded intratracheally with another anti-CD45 antibody (PE-Cy5-conjugated). Lungs were harvested, and single cell suspensions prepared for flow cytometric analysis using a panel of myeloid markers. This in vivo labelling protocol was also applied to mice exposed to acid-aspiration induced lung injury (3). To confirm the separation between the vascular and interstitial cell populations, a group of mice underwent intravenous labelling alone followed by lung perfusion for 15 minutes using an isolated-perfused lung apparatus (2).ResultsThe combined in vivo intravenous and intratracheal CD45 labelling enabled robust separation of the alveolar, interstitial, and vascular compartments of the lung by flow cytometry, with <0.3% of leukocytes staining

Conference paper

Woods SJ, Waite AAC, O'Dea KP, Halford P, Takata M, Wilson MRet al., 2015, Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L912-L921, ISSN: 1040-0605

Journal article

Lax S, Wilson MR, Takata M, Thickett DRet al., 2014, Using a non-invasive assessment of lung injury in a murine model of acute lung injury, BMJ Open Respiratory Research, Vol: 1, ISSN: 2052-4439

Arterial oxygen saturation has not been assessed sequentially in conscious mice as a direct consequence of an in vivo murine model of acute lung injury. Here, we report daily changes in arterial oxygen saturation and other cardiopulmonary parameters by using infrared pulse oximetry following intratracheal lipopolysaccharide (IT-LPS) for up to 9 days, and following IT-phosphate buffered saline up to 72 h as a control. We show that arterial oxygen saturation decreases, with maximal decline at 96 h post IT-LPS. Blood oxygen levels negatively correlate with 7 of 10 quantitative markers of murine lung injury, including neutrophilia and interleukin-6 expression. This identifies infrared pulse oximetry as a method to non-invasively monitor arterial oxygen saturation following direct LPS instillations.

Journal article

Soni S, Wilson MR, O'Dea K, Takata Met al., 2014, Microvesicles Are Sequentially Released From Different Intra-Alveolar Cells In A Mouse Model Of Acute Lung Injury, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Lax S, Wilson M, Takata M, Stewart P, Thickett Det al., 2013, The role of pre-receptor glucocorticoid metabolism in regulating the severity and persistence of murine lung injury, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Wakabayashi K, Wilson M, Tatham K, O'Dea K, Takata Met al., 2013, High-stretch, but not atelectasis, causes systemic cytokine release by lung-marginated monocytes, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Wakabayashi K, Wilson MR, Tatham KC, O'Dea KP, Takata Met al., 2013, Volutrauma, but not Atelectrauma, Induces Systemic Cytokine Production by Lung-Marginated Monocytes, Critical Care Medicine

Journal article

Patel BV, Wilson MR, O'Dea KP, Takata Met al., 2013, TNF-Induced Death Signaling Triggers Alveolar Epithelial Dysfunction in Acute Lung Injury, J Immunol, Vol: 190, Pages: 4274-4282

Journal article

Wilson MR, Takata M, 2013, Inflammatory mechanisms of ventilator-induced lung injury: a time to stop and think?, Anaesthesia, Vol: 68, Pages: 175-178

Journal article

Wakabayashi K, Wilson MR, Patel BV, Morley PJ, Baycliffe A, Takata Met al., 2013, Inhibition Of TNF Receptor p55 By A Domain Antibody Attenuates Acid-Induced Lung Injury In Mice, American Thoracic Society

RationaleTumor necrosis factor (TNF) is strongly implicated in the evolution of acute lung injury (ALI), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two cell surface receptors, p55 and p75, which play differential roles in ALI, with p55 promoting injury while p75 opposes this. We have recently shown that selective p55 blockade using novel domain antibody technology attenuates ventilator-induced lung injury (VILI) in mice. To further translate these findings to the bedside, we explored the potential for selective blockade of p55 in a clinically relevant mouse model of acid-induced ALI.MethodsMale C57BL6 mice were pretreated with intranasal administration of either specific domain antibody to p55 (dAb) or non-specific control domain antibody (‘dummy’). Four hours later, the mice were either instrumented for analysis without further instillation (i.e. baseline) or intratracheally challenged with hydrochloric acid (0.1M, 75μl) via an oro-tracheal tube to induce ALI. All acid-challenged animals were instrumented for analysis at 24 hours after acid instillation. Analysis consisted of mice being anesthetized, tracheostomized, and mechanically ventilated in order to evaluate PaO2/FiO2 ratio and respiratory mechanics. The left lung was taken for determining wet/dry ratio and a lunglavage sample was taken from the right lung to measure protein levels and neutrophil counts.ResultsHydrochloric acid instillation in the dummy group resulted in severe ALI, represented by hypoxemia, elastance increase, pulmonary edema and inflammation (Table 1). These mice were also visually very sick, showing considerably reduced locomotion and responsiveness. In contrast, pretreatment with p55 dAb dramatically improved the clinical symptoms, along with significant attenuation in all the physiological markers of lung injury. However, the dAb treatment did not significantly attenuate lung neutrophil recruitment represented b

Conference paper

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