Response-to-injury hypothesis | definition of response …
and is central to the “response to injury” hypothesis of ..
The modified response-to-injury hypothesis of atherosclerosis ..
The metabolic response to injury plays a unique role in all of these phases of critical illness. One could hypothesize that this metabolic response has not always evolved to lead to optimal long-term survival from prolonged ICU care.
The effect of turbulent blood flow on the arterial wall deserves special comment, particularly because it can be such an early influence. Arterial segments that are subject to turbulent blood flow, such as those at branch points or during hypertension, show a predisposition to lesion development, though the precise relationship in vivo may be complicated. Because of the response-to-injury hypothesis, the connection between blood flow and atherogenesis has led to many studies on the effects of shear stress on the endothelium in cell culture experiments. Many alterations have been reported,, , such as intracellular calcium mobilization, ion channel activation, cytoskeletal changes, altered cellular alignment, cell surface streamlining, increased endothelial cell division, stimulation of specific transcription factors, and production of potentially atherogenic molecules, such as vasoactive, adhesive, and growth, , factors. Somewhat different results are obtained in vitro when shear is low instead of high, constant instead of pulsatile, laminar instead of turbulent, or spatially uniform instead of graded,, , but the overall findings in vitro strongly support a contributory role for shear stress–induced alterations of the endothelium during atherogenesis.
by means of the “response to injury” hypothesis
We therefore propose that the atherogenic effects of sheer stress in vivo are entirely dependent on lipoprotein retention within the arterial wall and are limited to increased local vulnerability to lipoprotein retention and the consequences thereof. Specifically, we hypothesize that the role of shear stress in early atherogenesis is mediated primarily through the stimulation of intramural synthesis of molecules, such as proteoglycans, that promote lipoprotein retention (see References 63, 64, 66, 70, and 71, , , , ). Later, once vessel segments have accumulated retained lipoproteins, the threshold for injury and activation from continued shear stress may be lowered. Many stimuli can activate endothelial cells, and synergy is likely between shear stress and, for example, oxidative breakdown products of retained lipoproteins. The same general lines of reasoning can be used to argue against a central role for other potential activators of the endothelium, such as viruses or homocysteine,, , , which are likewise neither necessary nor sufficient for lesion development in vivo. Note that these hypotheses about the central role of retained lipoproteins are testable (see “Future Directions”).
A refinement of the response-to-injury hypothesis states that endothelial injuries that are insufficient to cause gross denudation but severe enough to cause functional modifications are key to atherogenesis., , , A major hypothesized change in endothelial function was increased permeability,, particularly to atherogenic lipoproteins., , , , This idea is related to the lipid infiltration hypothesis, which originated with Anichkov and Khalatov (reviewed in References 29 and 30, ). Alterations in permeability or even microscopic losses of endothelial cells in excess of those due to normal cell turnover are not mechanistically required for atherogenesis, however, because normal, healthy endothelium transports, or “leaks”, many molecules, including lipoproteins (reviewed in Reference 27). In fact, the rate of LDL entry into the normal, healthy arterial wall vastly exceeds the LDL accumulation rate. Most important, seminal studies by Schwenke and Carew, showed in vivo that the early prelesional accumulation of atherogenic lipoproteins within the arterial wall is focally concentrated in sites that are known to be prone to the later development of atheromata, but that the rates of lipoprotein entry into prelesional susceptible versus resistant sites were not different (cf Reference 2). These studies indicate that retention, not enhanced endothelial permeability to lipoprotein influx, is the key pathological event in this experimental model. Subsequent studies in several other animal models have demonstrated either increased, , , or decreased rates of lipoprotein entry into atherosclerosis-susceptible sites, suggesting a nonessential role for alterations in endothelial permeability. All studies agree, however, that prelesional susceptible arterial sites show enhanced retention of apoB-rich, atherogenic lipoproteins., , , , , We conclude that alterations in endothelial permeability, though apparently not essential to lesion development, may play a contributory role, eg, in smoking, dyslipidemias, (cf Reference 36), and possibly hypertension (cf Reference 43), but only if some of the infiltrated material is retained.
response to injury” model of atherogenesis ..
Despite the multifactorial nature of atherosclerosis, substantial evidence has established inflammation as an often surreptitious, yet critical and unifying driving force which promotes disease progression. To this end, research has defined molecular networks initiated by cytokines, growth factors and other pro-inflammatory molecules which promote hallmarks of atherosclerosis such as endothelial dysfunction, macrophage infiltration, LDL oxidation, cell proliferation and thrombosis. Although commonly associated with risk factors such as dyslipidemia, diabetes and hypertension, the global etiology of atherosclerosis may be alternatively attributed to underlying anthropological pressures. The agricultural, industrial and technological revolutions produced alterations in dietary, social and economic factors which have collectively exaggerated the exposure of the human genome to environmental stimuli. Furthermore, advances in sanitation, nutrition, and medicine have increased the lifespan of humans, effectively prolonging blood vessel exposure to these factors. As a result, the vasculature has become conditioned to respond to injury with what is arguably an overzealous immunological response; thus setting the stage for the prevalence of cardiovascular disease, including atherosclerotic plaque development in Western populations. Evidence suggests that each of these alterations can be linked to specific mediators in the inflammatory process. Integration of these factors with an inflammation-based hypothesis of atherosclerosis has yet to be extrapolated to observations in the realms of basic and clinical sciences and is the focus of this review.
platelets are not the sole initiators of smooth muscle proliferation, since growth promoting and growth inhibitory factors secreted by other cell types, including macrophages and endothelial cells, may modulate smooth muscle growth.However, not all observations made can be explained by the "response to injury" hypothesis, including the findings that (intimal) smooth muscle cells themselves can secrete and can respond to growth modulating factors and the cell transforming potential of plaque DNA as demonstrated above, thus implying an involvement of autocrine growth stimuli.
Many processes have been implicated in early atherogenesis
Pathogenesis of Atherosclerosis - SPH | Boston University
Pathogenesis contemporary view of atherogenesis is expressed by the response-to-injury hypothesis ..
Atherosclerosis is a disease process which is ..
The Response to Injury Theory
An evidence for “response to injury” hypothesis
AN EVIDENCE FOR "RESPONSE TO INJURY" HYPOTHESIS ..
Atherogenesis is related to macrophage accumulation within ..
Inflammation-based arterial changes as a mechanism of primary importance in atherogenesis was originally proposed in the mid-19th century by Rudolf Virchow. Since this seminal proposal, many hypotheses have emerged to incorporate the role of inflammation in this disease, such as Russell Ross’s commonly cited “response to injury” model of atherogenesis. Under this model, injury to the endothelium due to mechanical trauma, sheer stress, infection, and/or an increase in reactive oxygen species (ROS) is believed to be the initial trigger for a local inflammatory response., The inflammatory mediators that direct, perpetuate, and magnify disease progression can be categorized by both cell type(s) of origin and temporal relevance to disease stage .
laden macrophages and a few T lymphocytes
Throughout disease progression, silent plaque rupture and thrombosis may occur repeatedly without symptoms. However, these cycles ultimately serve to enhance fibrotic healing, SMC proliferation and to further amplify the inflammatory response. Paradoxically, repetitive cycles of inflammation and resolution may set the stage for a cataclysmic cardiovascular event. In fact, anti-inflammatory mechanisms are continuously evoked to maintain equilibrium. Anti-inflammatory cytokines IL-4, IL-10, and IL-13 may delay plaque formation by interfering at multiple time points during atherogenesis. For example, IL-10 has been demonstrated to suppress NF-κB activity and associated pro-inflammatory cytokine production in RAW 264.7 macrophages via a reduction in ROS generation. In addition to the role of platelets in thrombosis, animal models of atherosclerosis have demonstrated platelet adherence in the absence of endothelial injury and lesion development, suggestive of a role for these cells in the earlier stages of disease.
response-to-injury hypothesis explanation free
Hence, molecular alterations underlying the proliferation of smooth muscle cells could show resemblance to the molecular events, which are critical in the development of cancer.The current view on atherosclerosis is based on the "response to injury" hypothesis, implying a paracrine stimulation of smooth muscle growth as a result of injury of endothelium (Ross, et al., 1976; Ross, 1981).
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