Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44.

Svee, Kent; White, James G.; Vaillant, Pierre; Jessurun, José; Roongta, Urvashi V.; Krumwiede, Marci; Johnson, Debra; Henke, Craig A.

doi:10.1172/jci118970

Cited by 110 publications

(97 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Diverse cellular functions have been attributed to CD44, including involvement in leukocyte chemotaxis and activation (23), clearance of apoptotic cells and matrix fragments (6,24), resolution of chronic inflammation (6), regulation of fibrous tissue deposition (11), and angiogenesis (25). The present study reports the first evidence that CD44 plays an essential role in infarct healing and regulates postinfarction cardiac remodeling.…”

Section: Discussionmentioning

confidence: 83%

“…Second, CD44 deficiency may result in impaired fibroblast migration and invasion of the provisional matrix in the infarct. Svee et al (11) demonstrated that anti-CD44 Ab blocked fibroblast migration on the provisional matrix proteins fibronectin, fibrinogen, and HA, all important components of the healing wound (13). Third, CD44 may promote fibroblast survival by decreasing apoptosis (32).…”

Section: Role Of Cd44 In Fibrous Tissue Deposition In the Healing Infmentioning

confidence: 99%

“…CD44-hyaluronan interactions play an important role in regulating leukocyte extravasation into inflammatory sites (8,9) and mediate efficient phagocytosis (10). In addition, 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 (6), and mediates fibroblast migration and invasion in the wound provisional matrix (11). Although numerous studies have explored the significance of CD44-mediated interactions in a variety of inflammatory and fibrotic processes, the role of CD44 signaling in healing myocardial infarcts has not been investigated.…”

mentioning

confidence: 99%

See 2 more Smart Citations

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Huebener

Abou-Khamis

Zymek

et al. 2008

The Journal of Immunology

164

151

View full text Add to dashboard Cite

Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of “stop signals” that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44−/− animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44null infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44null cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-β in comparison to wild-type fibroblasts. The healing defects in CD44−/− mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Role Of Cd44 In Fibrous Tissue Deposition In the Healing Infmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Huebener

Abou-Khamis

Zymek

et al. 2008

The Journal of Immunology

164

151

View full text Add to dashboard Cite

show abstract

“…Recent data indicate that CD44 may be related to fibroblast migration and pulmonary repair after injury. CD44 is the surface receptor for matrix proteins supporting cell motility, including fibronectin and hyaluronan [28], and its expression is increased in hypertrophic scar fibroblasts [29]. Interestingly, lung tissues from patients with acute alveolar fibrosis revealed CD44-expressing mesenchymal cells through newly formed fibrotic tissue and high concentrations of this surface protein were found along the motile structures (filopodia and lamellopodia) of fibroblasts [28].…”

Section: Discussionmentioning

confidence: 99%

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

Silvestri¹,

Fregonese²,

Sabatini³

et al. 2001

Eur Respir J

View full text Add to dashboard Cite

b 2 -adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma.Since fibroblasts express b 2 -adrenoreceptors, the effects of different concentrations (0.1 -100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FPzS) on lung fibroblast proliferation and adhesion molecule expression were evaluated.Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-3 H] thymidine ([ 3 H]TdR) uptake, four-fold higher than that of control cultures (p~0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1 -100 nM; pv0.05). No changes in bFGFinduced cell proliferation were observed in the presence of FP (0.1 -100 nM; pw0.05, all comparisons). In addition, the association FPzS did not improve the inhibitory activity of S alone (pw0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor-a (TNF-a) (p~0.0004), but not by interleukin-4 (IL-4) (pw0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (pw0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1 -100 nM; pv0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (pv0.01), but not on H-CAM expression (pw0.1).These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.

show abstract

“…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]. Recent experiments from our laboratory tested the hypothesis that CD44 may play an essential role in infarct healing by regulating the inflammatory and fibrotic response [286].…”

Section: Clearance Of Apoptotic Neutrophils and Removal Of Matrix Debrismentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

View full text Add to dashboard Cite

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.

show abstract

Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44.

Cited by 110 publications

References 28 publications

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

Fluticasone and salmeterol downregulatein vitro, fibroblast proliferation and ICAM-1 or H-CAM expression

The immune system and cardiac repair

Contact Info

Product

Resources

About