Resolution of Lung Inflammation by CD44

Teder, Priit; Vandivier, R. William; Jiang, Dianhua; Liang, Jiurong; Cohn, Lauren; Puré, Ellen; Henson, Peter M.; Noble, Paul W.

doi:10.1126/science.1069659

Cited by 608 publications

(595 citation statements)

References 18 publications

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“…27,28 Increasing evidence suggests that apoptotic mechanisms may play important roles in the resolution of inflammation. 29,30 One can therefore expect tight correlation between apoptosis and the activation of TGF-b.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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Transforming growth factors b (TGF-bs) are multifunctional cytokines that modulate cell growth, differentiation and apoptosis. Numerous effects initiated by TGF-bs in vitro have been described, but the role of TGF-b targeting and activation under physiological conditions has gained very little attention and understanding. We report here that apoptosis of human umbilical vein endothelial cells (HUVECs) is accompanied by release of truncated large latent TGF-b complexes from the pericellular matrix followed by activation of TGF-b. The activation of TGF-b during apoptosis was accompanied by enhanced secretion of b1-LAP protein, and apoptotic HUVECs acquired the capacity to induce the release of latent TGF-bbinding proteins (LTBPs) from extracellular matrices. Activated TGF-b, in turn, attenuated apoptotic death of HUVECs. Current results indicate that the activation of TGF-b accompanies the apoptosis of HUVECs, and may play a protective feedback role against apoptotic cell death. The results suggest a role for TGF-b as a putative extracellular modulator of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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“…Hyaluronan fragments induce the expression of a variety of inflammatory genes by endothelial cells and macrophages [282], including chemokines and cytokines, and may play an important role in regulating inflammatory processes. Furthermore, clearance of hyaluronan fragments from the injured tissue is crucial for resolution of chronic inflammation [283]. Hyaluronan modulates the inflammatory response through interactions with the transmembrane adhesion molecule CD44 [284], a ubiquitously distributed glycoprotein that mediates a wide variety of cell-cell and cell-matrix interactions.…”

Section: Clearance Of Apoptotic Neutrophils and Removal Of Matrix Debrismentioning

confidence: 99%

“…Hyaluronan modulates the inflammatory response through interactions with the transmembrane adhesion molecule CD44 [284], a ubiquitously distributed glycoprotein that mediates a wide variety of cell-cell and cell-matrix interactions. A growing body of evidence suggests that CD44 serves as a key factor in resolution of inflammation through removal of matrix breakdown products and clearance of apoptotic neutrophils [283]. CD44 also exerts fibrogenic actions mediating fibroblast migration and invasion in the wound provisional matrix [285].…”

Section: Clearance Of Apoptotic Neutrophils and Removal Of Matrix Debrismentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

563

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…This model has previously been used to evaluate efferocytosis by macrophages and epithelial cells in vivo (45,50). Defective efferocytosis is suggested by either decreased uptake into alveolar macrophages (i.e., decreased PI; Fig.…”

Section: Lovastatin Increases Efferocytosis In Vivomentioning

confidence: 99%

“…Phagocytosis was determined by visual inspection of samples (see Fig. 5A), as previously described (45,50), and was expressed a PI. A minimum of 400 alveolar macrophages were counted blindly.…”

Section: In Vivo Phagocytosis Assaysmentioning

confidence: 99%

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Morimoto

Janssen²,

Fessler³

et al. 2006

The Journal of Immunology

Self Cite

198

179

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Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

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Resolution of Lung Inflammation by CD44

Cited by 608 publications

References 18 publications

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

The immune system and cardiac repair

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

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