Adenosine receptor A<sub>2b</sub> on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium

Konrad, Franziska M.; Witte, E.; Vollmer, Irene; Stark, Stefanie; Reutershan, Jörg

doi:10.1152/ajplung.00387.2011

Cited by 36 publications

(48 citation statements)

References 57 publications

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“…A 2B R signaling has been reported to be broadly antiinflammatory in several models of acute lung injury; in particular, A 2B R deficiency is associated with increased lung inflammation after challenge with bleomycin, LPS, ischemia-reperfusion, and ventilator-associated lung injury (29,(36)(37)(38). The reported mechanisms of these effects have varied markedly between these models and have included alteration of leukocyte traffic, reduction in vascular permeability mediated by bone marrow-derived cells, and attenuation of the neutrophil oxidative burst (14,37,38); on the other hand, work has shown A 2B R expression on bone marrow-derived cells to paradoxically enhance neutrophil migration to the lung interstitium in response to LPS (39). We speculate that the reported differences in the mechanisms of A 2B R effects in these models reflect differences in dynamics of production and degradation of adenosine, and differences in the number of adenosine-responsive cells as well as their adenosine receptor repertoire in the context of different injuries.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Barletta¹,

Cagnina

Burdick

et al. 2012

Am J Respir Crit Care Med

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Rationale: Activation of the adenosine A 2B receptor (A 2B R) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance. Objectives: To test the hypothesis that absence of adenosine A 2B receptor signaling promotes host defense against bacterial pneumonia. Methods: We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A 2B R. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro. Measurements and Main Results: A 2B R -/-mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow-derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A 2B R -/-and wild-type mice, but A 2B R -/-neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A 2B R -/-mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia. Conclusions: These data suggest that the absence of A 2B R signaling enhances antimicrobial activity in gram-negative bacterial pneumonia.Keywords: neutrophil; extracellular traps; pneumonia; adenosine Pneumonia is a leading cause of hospitalization in the United States and is the most common infectious cause of death (1, 2). Aerobic gram-negative bacilli are the most common cause of health care-associated pneumonia; mortality rates from gram-negative pneumonia range from 30 to 60% with antimicrobial therapy (3, 4). The emergence of multiresistant strains of gram-negative bacteria, combined with limited development of new antimicrobial therapies, has exacerbated the need for new approaches to combating these pathogens (5-7). Therapy aimed at augmenting the host response has the potential to enhance bacterial clearance and improve outcomes, and could provide a new avenue for therapeutic advances in combating gramnegative pneumonia, including infections that are caused by antibiotic-resistant pathogens.Adenosine, a breakdown product of ATP, is a potent signaling molecule released from a variety of cells to dampen inflammation, limit tissue destruction, and promote repair (8, 9). In response to cellular stress or tissue injury, the extracellular concentration of adenosine can increase 100-fold. Adenosine acts on four widely expressed G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 , with variable expression among different cells. The adenosine A 2B receptor (A 2B R) has been shown to en...

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Section: Discussionmentioning

confidence: 99%

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Barletta¹,

Cagnina

Burdick

et al. 2012

Am J Respir Crit Care Med

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“…Neutrophils are marginated in the alveolar capillaries in infectious or noninfectious ALI, and this process involves engagement of chemokine-receptor interactions (267) and of different families of endothelial and epithelial adhesion molecules, such as JAMs (junctional adhesion molecules), ICAM-1 (intercellular adhesion molecule-1), PECAM-1 (platelet endothelial cell adhesion molecule-1), and VCAM-1 (vascular adhesion molecule-1), which are upregulated upon release of inflammatory mediators like TNF-␣ (16,93,131). In addition, leukocyte-expressed adenosine receptor A(2b) and eicosanoid expression are attributed a role in pulmonary neutrophil recruitment in LPS-induced ALI or after Pseudomonas aeruginosa infection in mice (102,124). Once recruited into the alveolar compartment, neutrophils release proteases or neutrophil extracellular traps composed of chromatin and antimicrobial agents, which may cause endo-or epithelial injury (163,201).…”

Section: Immune Cells and Inflammatory Signaling Pathways In Alimentioning

confidence: 99%

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

Herold

Gabrielli

Vadász

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

177

178

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Herold S, Gabrielli NM, Vadász I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 305: L665-L681, 2013. First published September 13, 2013 doi:10.1152/ajplung.00232.2013In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means. alveolar-capillary barrier dysfunction; molecular mechanism; pharmacological and cell-based therapy; pulmonary edema; zaacute lung injury/acute respiratory distress syndrome Immune Cells and Inflammatory Signaling Pathways in ALIOne of the central concepts in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that an unbalanced quantity or quality of the inflammatory response aggravates epithelial or endothelial injury. This includes a dysregulated recruitment of leukocytes and/or an exaggerated activation of these cells; inappropriate expression of cytokines, lipid mediators, or reactive oxygen species; enhanced activation of death receptor signaling (97,98,140,207,240); or an uncontrolled activity of platelets or the coagulation cascade (154). In general, these responses are initiated and maintained by recognition of danger-or pathogen-associated molecular patterns

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“…In addition, lung edema is prominent in seawater induced ALI because high osmotic seawater pull water through vascular endothelial cells and alveolar epithelial cells [4], [5]. It has been reported that increased alveolar epithelial and pulmonary microvascular endothelial permeability trigger the transmigration of inflammatory cells such as neutrophils and the formation of edema fluid [6]. Accordingly, inhibition of inflammation and lung tissue barrier permeability may be propitious to the promotion of seawater aspiration-induced ALI.…”

Section: Introductionmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

et al. 2014

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IntroductionInflammation and pulmonary edema are involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have reported that 1α,25-Dihydroxyvitamin D3 (calcitriol) suppresses inflammation, it has not been confirmed to be effective in seawater aspiration-induced ALI. Thus, we investigated the effect of calcitriol on seawater aspiration-induced ALI and explored the probable mechanism.MethodsMale SD rats receiving different doses of calcitriol or not, underwent seawater instillation. Then lung samples were collected at 4 h for analysis. In addition, A549 cells and rat pulmonary microvascular endothelial cells (RPMVECs) were cultured with calcitriol or not and then stimulated with 25% seawater for 40 min. After these treatments, cells samples were collected for analysis.ResultsResults from real-time PCR showed that seawater stimulation up-regulated the expression of vitamin D receptor in lung tissues, A549 cells and RPMVECs. Seawater stimulation also activates NF-κB and RhoA/Rho kinase pathways. However, we found that pretreatment with calcitriol significantly inhibited the activation of NF-κB and RhoA/Rho kinase pathways. Meanwhile, treatment of calcitriol also improved lung histopathologic changes, reduced inflammation, lung edema and vascular leakage.ConclusionsThese results demonstrated that NF-κB and RhoA/Rho kinase pathways are critical in the development of lung inflammation and pulmonary edema and that treatment with calcitriol could ameliorate seawater aspiration-induced ALI, which was probably through the inhibition of NF-κB and RhoA/Rho kinase pathways.

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Adenosine receptor A_2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium

Abstract: Konrad FM, Witte E, Vollmer I, Stark S, Reutershan J. Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium.

Cited by 36 publications

References 57 publications

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

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Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium

Abstract: Konrad FM, Witte E, Vollmer I, Stark S, Reutershan J. Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium.

Cited by 36 publications

References 57 publications

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

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Adenosine receptor A_2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia