Is Overamplification of the Normal Macrophage Defensive Role Critical to Lesion Development?<sup>a</sup>

Raines, Elaine W.; Ross, Russell

doi:10.1111/j.1749-6632.1997.tb51991.x

Cited by 11 publications

(3 citation statements)

References 43 publications

(43 reference statements)

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“…Experiments by others using flow through small diameter tubing, or capillary viscometers, found that platelets became activated when exposed to much higher shearing forces (300 to 1000 dyne/cm 2 ) but for only very brief durations (0.02 to 2 s). 40 Hellums later consolidated the findings from several groups using different flow devices to show that shear-induced platelet activation, as measured by serotonin release, was a function of both the shear stress magnitude and exposure time. 41 Boreda 42 later derived a platelet stimulation function such that platelet stimulation functionϭϫt 0.452 , where the activation state was linearly dependent on the magnitude of shear stress exposure () and somewhat less dependent on duration (t).…”

Section: Platelets and High Shear Environmentsmentioning

confidence: 87%

Flow Effects on Coagulation and Thrombosis

Hathcock¹

2006

ATVB

339

281

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Abstract-Thrombosis occurs in a dynamic rheological field that constantly changes as the thrombus grows to occlusive dimensions. In the initiation of thrombosis, flow conditions near the vessel wall regulate how quickly reactive components are delivered to the injured site and how rapidly the reaction products are disseminated. Whereas the delivery and removal of soluble coagulation factors to the vessel is thought to occur via classic convection-diffusion phenomena, the movement of cells and platelets to the injured wall is strongly augmented by flow-dependent cell-cell collisions that enhance their ability to interact with the wall. In addition, increased shear conditions have been shown to activate platelets, alter the cellular localization of proteins such as tissue factor (TF) and TF pathway inhibitor, and regulate gene production. In the absence of high shearing forces, red cells, leukocytes, and platelets can form stable aggregates with each other or cells lining the vessel wall, which, in addition to altering the biochemical makeup of the aggregate or vessel wall, effectively increases the local blood viscosity. Thus, hemodynamic forces not only regulate the predilection of specific anatomic sites to thrombosis, but they strongly influence the biochemical makeup of thrombi and the reaction pathways involved in thrombus formation. T hrombosis is thought to begin with an event such as plaque rupture, vessel damage, or dysfunctioning endothelium, resulting in the exposure of active tissue factor (TF) on the vessel wall. 1 The exposed TF binds circulating factor VII/VIIa (fVII/fVIIa) with high-affinity (Kd Ͻ10 pM), forming a reactive vessel surface that proteolytically cleaves fIX and fX. The rate of this surface-bound reaction depends not only on biochemical factors (number and surface density of TF:VIIa complexes, intrinsic kinetic activity, and local phospholipid composition 2 ) but on the rate at which the substrates fIX and fX are transported by the flowing medium to the reactive surface 3 and the rate at which product is removed. 4 Moreover, the local accumulation of reaction product may be critical in overpowering endogenous inhibitors and successfully initiating coagulation.Although convective flow forces dominate the axial movement of blood components (coagulation factors, platelets, red cells, leukocytes, and inhibitors) throughout most of the body, in the few microns approaching the vessel wall where thrombosis is thought to initiate, the frictional drag of the vessel wall causes the axial flow velocity to slow to 0, and the convective and diffusive motion of blood components becomes comparable. 5 In this initial coagulation reaction, blood flowing parallel to the wall convectively transports coagulation factors (fIX and fX) from upstream to a region close to the reactive site, and Brownian motion mediates the radial movement toward the reactive wall. In the case of platelets adhering to the wall, a similarly defined adhesion rate is often inferred. 6 The bound proteins fIX and fX become proteolyt...

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Section: Platelets and High Shear Environmentsmentioning

confidence: 87%

Flow Effects on Coagulation and Thrombosis

Hathcock¹

2006

ATVB

339

281

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“…Certainly, monocytes/macrophages are intimately involved in plaque rupture. 2,27 As monocytes differentiate in the subintima into macrophages and foam cells, the atherogenic microenvironment influences transcriptional regulation of genes, the products of which will determine the natural history of the lesion. 1 MMPs furnish one example of proteins, the induction and expression of which by monocytes/macrophages likely contributes to subsequent plaque rupture.…”

Section: Discussionmentioning

confidence: 99%

Macrophages in Human Atheroma Contain PPARγ

Marx¹,

Sukhova²,

Murphy³

et al. 1998

The American Journal of Pathology

496

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Mononuclear phagocytes play an important role in atherosclerosis and its sequela plaque rupture in part by their secretion of matrix metalloproteinases (MMPs), including MMP-9. Peroxisomal proliferator-activated receptor gamma (PPARgamma), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-delta12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPARgamma in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPARgamma. Normal artery specimens (n = 6) reveal minimal immunoreactive PPARgamma. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPARgamma mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPARgamma mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPARgamma with troglitazone or 15-deoxy-delta12,14-prostaglandin J2 in human monocyte-derived macrophages inhibited MMP-9 gelatinolytic activity in a concentration-dependent fashion as revealed by zymography. This inhibition correlates with decreased MMP-9 secretion as determined by Western blotting. Thus, PPARgamma is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPARgamma is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.

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“…The mechanisms that appear to be responsible for this increased proliferative response are growth factors, cytokines, and local alterations in the extracellular matrix proteins. There is increasing evidence that atherosclerosis should be viewed fundamentally as an inflammatory disease (Raines and Ross 1997) where risk factors such as hypertension, humoral factors (Raij 1991), hyperlipidemia (Devaraj and Jialal 1996), lipid deposition in vessels and later development of atherosclerotic lesions play central roles in the progression. As in the case of atherosclerosis, there is an inflammatory content involved in kidney fibrosis in human (Noronha, Niemir et al 1995) or experimental glomerulonephritides (Lloyd, Minto et al 1997), and even in classical glomerulosclerotic models previously thought to be non-inflammatory, e.g.…”

Section: Progression Of Ckdmentioning

confidence: 99%

Chronic Kidney Disease

Ots¹

2010

Health Management

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Is Overamplification of the Normal Macrophage Defensive Role Critical to Lesion Development?^a

Cited by 11 publications

References 43 publications

Flow Effects on Coagulation and Thrombosis

Flow Effects on Coagulation and Thrombosis

Macrophages in Human Atheroma Contain PPARγ

Chronic Kidney Disease

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Is Overamplification of the Normal Macrophage Defensive Role Critical to Lesion Development?a

Cited by 11 publications

References 43 publications

Flow Effects on Coagulation and Thrombosis

Flow Effects on Coagulation and Thrombosis

Macrophages in Human Atheroma Contain PPARγ

Chronic Kidney Disease

Contact Info

Product

Resources

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Is Overamplification of the Normal Macrophage Defensive Role Critical to Lesion Development?^a