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1.  Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury 
Mucosal immunology  2013;7(2):440-448.
Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin-1 (thbs1−/−), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to LPS-induced lung injury and show defective macrophage IL-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1−/− mice from persistent neutrophilic lung inflammation and injury and thbs1−/− alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co-culture with apoptotic neutrophils, thbs1−/− macrophages show a selective defect in IL-10 production whereas PGE2 and TGF-β1 responses remain intact. Full macrophage IL-10 responses require the engagement of thrombospondin-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages.
doi:10.1038/mi.2013.63
PMCID: PMC3945733  PMID: 24045574
Thrombospondin-1; Injury Resolution
2.  Pharmacologic Activation of the Innate Immune System to Prevent Respiratory Viral Infections 
Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compound called 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immune activation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-β and subsequent high-level induction of IFN-β–dependent proteins, such as myxovirus resistance 1 (Mx1) and 2′,5′-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-β system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and “first responders” in the early stages of viral pandemics or bioterror attacks.
doi:10.1165/rcmb.2010-0288OC
PMCID: PMC3265219  PMID: 21148741
innate immunity; interferon; influenza; pneumonia; bronchial epithelium
3.  Duffy Antigen Receptor for Chemokines Mediates Chemokine Endocytosis through a Macropinocytosis-Like Process in Endothelial Cells 
PLoS ONE  2011;6(12):e29624.
Background
The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear.
Methodology/Principal Findings
We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated 125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. 125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression. 125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells.
Conclusions/Significance
These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization.
doi:10.1371/journal.pone.0029624
PMCID: PMC3246497  PMID: 22216333
4.  Advanced Glycation Endproducts on Stored Erythrocytes increase Endothelial Reactive Oxygen Species Generation through Interaction with RAGE 
Transfusion  2010;50(11):2353-2361.
Background
Recent evidence suggests that storage induced alterations of the red blood cell (RBC) are associated with adverse consequences in susceptible hosts. As RBCs have been shown to form Advanced Glycation Endproducts (AGEs) following increased oxidative stress and under pathologic conditions, we examined whether stored RBCs undergo modification with the specific AGE, N-(Carboxymethyl)lysine (Nε-CML) during standard blood banking conditions.
Study Design and Methods
Purified, fresh RBCs from volunteers were compared to stored RBCs (d 35–42 old) obtained from the Blood Bank. Nε-CML formation was quantified using a competitive enzyme-linked immunosorbent assay. The receptor for advanced glycation end-products (RAGE) was detected in human pulmonary microvascular endothelial cells by real-time PCR, western blotting, and flow cytometry. Intracellular reactive oxygen species (ROS) generation was measured by the use of 5-(and 6-)chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester based assays.
Results
Stored RBCs showed increased surface Nε-CML formation when compared with fresh RBCs. Human Pulmonary Microvascular Endothelial Cells (HMVEC-L) showed detectable surface RAGE expression constitutively. When compared to fresh RBCs, stored RBCs triggered increased intracellular ROS generation in both Human Umbilical Vein Endothelial Cells (HUVEC) and Human Pulmonary Microvascular Endothelial Cells (HMVEC-L). RBC-induced endothelial ROS generation was attenuated in the presence of soluble RAGE (sRAGE) or RAGE blocking antibody.
Conclusion
The formation of the AGE Nε-CML on the surface of stored RBCs is one functional consequence of the storage lesion. AGE-RAGE interactions may be one mechanism by which transfused RBCs cause endothelial cell damage.
doi:10.1111/j.1537-2995.2010.02689.x
PMCID: PMC3010325  PMID: 20492604
AGE (advanced glycation endproducts); Nε-CML (N-Carboxymethyl-lysine); RAGE (receptor for advanced glycation endproducts)
5.  Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction 
Rationale: The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.
Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.
Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) within the first 72 hours after transplantation.
Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's ρ = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).
Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.
doi:10.1164/rccm.200901-0118OC
PMCID: PMC2778153  PMID: 19661249
primary graft dysfunction; reperfusion injury; lung transplantation; receptor for advanced glycation end products; acute lung injury

Results 1-5 (5)