Publications
170 results found
Soni S, O'Dea K, Tan YY, et 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.
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
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
- Author Web Link
- Cite
- Citations: 1
Matsumoto S, Iki Y, Abe M, et 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
Tan YY, O'Dea KP, Soo AP, et 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
Antcliffe D, Wolfer A, O'Dea K, et 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.
Garner J, Soni S, O'Dea K, et 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
- Author Web Link
- Cite
- Citations: 1
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
Tatham KC, O'Dea KP, Romano R, et 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.
Nakamura H, Wilson MR, Yao K, et al., 2018, Modulation Of Mechanical Ventilation-Induced Alveolar Epithelial Cell Death Signaling By Underlying Lung Inflammation, American Thoracic Society 2018, Publisher: American Thoracic Society
Soni S, Wilson MR, Dea KPO, et 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
Mitsui Y, Dea KPO, Uchida T, et al., 2018, Pro-Inflammatory Activity of Granulocyte-Derived Microvesicles Is Potentiated by Endotoxin Pre-Stimulation, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Edey LF, Georgiou H, O'Dea KP, et 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.
Wilson MR, Petrie JE, Shaw MW, et 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.
Zöllner J, Howe LG, Edey LF, et 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.
Patel BV, Yao K, Nakamura H, et al., 2017, Distinct Differences In Alveolar Epithelial Cell Death Signalling Between Models Of Ards, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Tirlapur N, O'Dea K, Soni S, et 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
Oakley CM, Wilson M, O'Dea K, et 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
Tan YY, O'Dea KP, Soni S, et 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
Davies R, O'Dea KP, Soni S, et 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
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
Wilson MR, Wakabayashi K, Bertok S, et 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.
Takata M, Wilson M, 2017, 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.
O'Dea KP, Porter J, TIrlapur N, et al., 2016, Circulating microvesicles are elevated acutely following major burns injury and associated with clinical severity, PLOS One, Vol: 11, ISSN: 1932-6203
Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group.We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry.All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p=0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p=0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p=0.002; granulocyte MVs 4.8 fold, p=0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p=0.01) for total leukocyte microvesicles and 0.85 (p=0.04) for granulocyte microvesicles. These findings demonstrate, for the first t
Edey LF, O'Dea KP, Herbert BR, et al., 2016, The local and systemic immune response to intrauterine LPS in the prepartum mouse, Biology of Reproduction, Vol: 95, Pages: 1-10, ISSN: 1529-7268
Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 μg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFκB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta.
Takata M, Li H, Yao Z, et al., 2016, P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression, Stem Cell Research & Therapy, Vol: 7, ISSN: 1757-6512
Background:Epithelial to mesenchymal transition, especially to myofibroblasts, plays an important role in woundhealing, fibrosis, and carcinogenesis. Epidermal stem cells (EpSCs) are responsible for epidermal renewal and woundre-epithelialization. However, it remains unclear whether and how EpSCs transdifferentiate into myofibroblasts ormyofibroblast-like cells (MFLCs). Here, we provide the first evidence showing that P311 induces EpSC to MFLCtransdifferentiation (EpMyT) via TGFβ1/Smad signaling.Methods:Wound healing and mesenchymal features were observed in the P311 KO and P311 WT mouse modelof superficial second-degree burns. After the primary human or mouse EpSCs were forced to highly express P311using an adenoviral vector, EpMyT was observed by immunofluorescence, real-time PCR, and western blot. Theactivity of TGFβ1 and Smad2/3 in EpSCs with different P311 levels was observed by western blot. The TβRI/IIinhibitor LY2109761 and Smad3 siRNA were applied to block the EpMyT in P311-overexpressing EpSCs andexogenous TGFβ1 was to restore the EpMyT in P311 KO EpSCs. Furthermore, the mechanism of P311 regulatingTGFβ1 was investigated by bisulfite sequencing PCR, luciferase activity assay, and real-time PCR.Results:P311 KO mouse wounds showed delayed re-epithelialization and reduced mesenchymal features.ThehumanormouseEpSCswithoverexpressedP311exhibited fusiform morphological changes, upregulatedexpression of myofibroblast markers (α-SMA and vimentin), and downregulated expression of EpSC markers(β1-integrin and E-cadherin). P311-expressing EpSCs showed decreased TGFβ1mRNAandincreasedTGFβ1protein, TβRI/II mRNA, and activated Smad2/3. Moreover, LY2109761 and Smad3 siRNA reversed P311-inducedEpMyT. Under the stimulation of exogenous TGFβ1, the phosphorylation of Smad2 and Smad3 in P311 KO EpSCswas significantly lower than that in P311 WT EpSCs and the EpMyT in P311 KO EpSCs was restored. Furthermore,P311 enhanced the
Wilson MR, Takata M, John AE, et 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, Pages: 1-17, 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.
Soni S, Wilson MR, O'Dea KP, et 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.
Halford P, Woods S, Wilson M, et 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
Tatham KC, O'Dea KP, Romana R, et al., 2016, Retention And Activation Of Donor Vascular Monocytes In Transplanted Lungs Suggests A Central Role In Primary Graft Dysfunction, American Thoracic Society Conference 2016
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.