Microvascular alterations

H19. Henson, P. M Larsen, G. L., Webster, R. O., Mitchell, B. C., Goins, A. J., and Henson, J., Pulmonary microvascular alterations and injury induced by complement fragments Synergistic ef-... 

Algenstaedt P, Schaefer C, Biermann T, Hamann A, Scwarzloh B, Greten H, Ruther W, Hansen- Algenstaedt N. Microvascular alterations in diabetic mice correlate with level of hyperglycemia. Diabetes 2003, 52, 542-549. 

T. Reffemann and R.A. Kloner, Microvascular alterations after temporary coronary artery occlusion the no-reflow phenomenon, Cardiovasc. Pharmacol. Ther. 9(3), 163-172 (2004). 

Connective tissue, which consists primarily of fibroblasts, produces extracellular matrix materials that surround cells and tissues, determining their appropriate position within the organ (see Chapter 49). These materials include structural proteins (collagen and elastin), adhesive proteins (fibronectin), and glycosaminoglycans (heparan sulfate, chondroitin sulfate). The unique structures of the proteins and carbohydrates found within the extracellular matrix allow tissues and organs to carry out their many functions. A loss of these supportive and barrier functions of connective tissue sometimes leads to significant clinical consequences, such as those that result from the microvascular alterations that lead to blindness or renal failure, or peripheral neuropathies in patients with diabetes mellitus. 

Reference for severity categories of heart lesions 1, Abdellatif and Vies (1973) mild (1), moderate (2), definite (3), and severe (4) cellular and/or fibrotic scars 1, McCutcheon et al. (1976) fresh (1) and old (2) myocardial necrosis and microvascular alterations (3) 3, Astorg and Levillain (1979) histiocytes (1), granules (2), and granules and necrosis (3). 

McCutcheon etal., 1976 20 W 25 Microvascular alteration, fresh and old focal necrosis... 

Beon M, Harley RA, Wessels A, et al. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol 2004 22 733-742. Kuwana M, Kaburaki J, Mimori T, et al. Autoantigenic epitopes on DNA topoisomerase I. Clinical and immunogenetic associations in systemic sclerosis. Arthritis Rheum 1993 36 1406-1413. 

With modest impairment of blood flow, this mechanism allows for preservation of oxidative metabolism without alteration in electrical function. However, when CPP and therefore CBF are sufficiently low, OEF reaches a maximum and cannot increase further. Brain tissue ceases to function electrically, resulting in a neurologic deficit. Microvascular collapse occurs, and CBV falls. If the oxygen supply falls low enough, the tissue dies. Of critical clinical importance is the observation that the amount of time it takes for tissue to suffer irreversible damage is inversely related to the severity of the ischemic insult. Tissue that is completely deprived of blood will die within a few minutes, but less severely hypoperfused tissue may survive for many hours, and may be saved by timely thrombolysis that restores perfusion, or perhaps by another therapeutic intervention. 

Septic shock is frequently complicated by massive activation of the coagulation system. This can occur concomitantly with biphasic change in the fibrinolytic system, involving both activation and inhibition of plasminogen activation. The net result of the altered hemostatic state in sepsis is widespread microvascular trom-bosis. The early events leading to these disturbances are incompletely understood,... 

Pathological findings frequently observed in organs of patients who have died of sepsis include disseminated intravascular coagulation (DIC), manifested as diffuse thrombotic occlusions in the entire microvascular system, associated with alterations in the hemostatic mechanism and clinical signs of hemorrhagic diathesis. Many observations indicate that DIC contributes to the major symptoms of the systemic inflammatory response syndrome (SIRS), which frequently complicate sepsis (HI, H2, H3, T6). 

Looking at the results of both preclinical and clinical studies, we recognize the potential of cardiac cell transplantation to alter outcomes. However, we have to admit that in most cases, we do not understand how different cell types improve LV function. Increases in microvascular density, diastolic and systolic function, and an attenuated remodeling, are all reported after the application of many different cell types, but the exact mechanisms are unclear. Only a few studies address the elec-trophysiologic fate of the injected cells (71,72). In these studies, skeletal myoblasts were found to be isolated from the surrounding myocardium, and they underwent severe... 

New advances in microscopy and ophcs, computer software and fluorophores to label target molecules have allowed investigators to utilize intravital two-photon microscopy to study the dynamic events within the functioning kidney. This emerging technique enables investigators to follow functional and structural alterations with subceUular resolution within the same field of view over a short period of time. This technique will enable studies of microvascular function within the kidney [165-168]. 

The FVB-T1E2/GFP mouse, in which the endothelium is fluorescent, has heen used to study morphological changes in the renal microvascular endothelium during ischemia-reperfusion injury in the kidney [169]. Alterations in the cytoskeleton of renal microvascular endothelial cells correlated with a permeability defect in the renal microvasculature as identified using fluorescent dextrans and two-photon intravital imaging. This study demonstrates that renal vascular endothelial injury occurs in ischemic AKI and may play an important role in the pathophysiology of ischemic AKI. 

Button TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, Molitoris BA Injury ofthe renal microvascular endothelium alters barrier function after ischemia. American Journal of Physiology - Renal Fluid Electrolyte Physiology 285 F191-F198, 2003... 

The innervation of the lymphoid vasculature by substance P-containing neurons and the ability of substance P to enhance lymph tissue blood flow (Lundbeig et al., 1985) suggest that substance P may alter lymphocyte traffic . Substance P induces the expression of endothelial leukocyte adhesion molecule 1 (ELAM-1) on microvascular endothelial cells (Matis et al., 1990) and may similarly affect the expression of adhesion molecules on lymphocytes. Infusion of substance P has been shown to increase lymph flow and lymphocyte traffic in sheep lymph nodes (Moore etal., 1989). 

The effect of age on percutaneous absorption has been examined in vivo in man with variable results. It was postulated (Roskos et al. 1989) that reduced hydration levels and lipid content of older skin may be responsible for a demonstrated reduction in skin permeability where the permeants were hydrophilic in nature (no reduction was seen for model hydrophobic compounds) (Table 14.2). The reduced absorption of benzoic acid demonstrated in the elderly (Rougier 1991) was in line with this suggestion, but not the reduction in absorption of testosterone (lipophilic) (Roskos et al. 1986), or lack of change in the absorption of methyl nicotinate (more hydrophilic) with age (Guy et al. 1983). There are a number of potential physiological changes which may be responsible for age-related alterations, including an increase in the size of individual stratum corneum corneocytes, increased dehydration of the outer layers of the stratum corneum with age, decreased epidermal turnover and decreased microvascular clearance (reviewed in Roskos and Maibach 1992). The issue of age-related variability, however, is far from resolved. 

Also the secondary endpoints of microvascular comphcations were markedly altered 61% (Cl 13-83%) lower relative risk of nephropathy, 58% (Cl 14-79%) lower risk of retinopathy, and 63% (Cl 21-82%) lower risk of autonomic neuropathy. For the primary CVD endpoint risk reductions were seen for all the different components except for mortality. It may be added that this trial was not statistically powered to evaluate the interventional impact on mortality. 

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