Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

MEDICAL LITERATURE has been deluged during the past few years with books and papers on penicillin; but a book which has been produced under the general editorship of Sir Alexander Fleming himself represents a complete and authoritative summary of penicillin therapy as it stands today.' The book contains a series of independent contributions by \"experienced and eminent men who have worked with penicillin in Great Britain\". Their opinions and practical methods differ slightly, and there is some overlapping; but these are not disadvantageous, comparison and contrast lending interest to the reading. In the first or general section of the book Fleming contributes two chapters, one on the history and development of penicillin, introducing some interesting sidelights in the romance of discovery, the other on the bacteriological control of penicillin therapy. In both chapters the information is set out in meticulous detail and with a clarity and simplicity which can be enjoyed by all readers. Fleming also gives the right perspective to the place of penicillin amongst the antibiotics and lays down the principles of treatment. Both chapters are well illustrated and are the most outstanding in the book. Included in this first section also are chapters on the chemistry and manufacture of penicillin and its pharmacy, pharmacology and methods of administration. The second section of the book is entirely clinical, giving each author's view on the use of penicillin therapy in a disease or an infection of some particular region of the body. The entire range of peniCillin-sensitive conditions is considered in twenty authoritative and clearly written chapters; these contain many references and illustrations. Dental and veterinary diseases are also given fairly full consideration. The final section is a condensed resume of much of the preceding chapters and is written for. the general practttioner. This chapter is superttuous: it does not contain enough detall to be of much practical value. The book as a Whole, however, will undoubtedly be considered a classical contribution to medical literature and is strongly recommended, not only because of the general interest of its topic, but as a reference book on penicillin therapy of hitherto unequalled excellence. The typography, although conforming to war economy standards, is clear and the paper is good. There is an excellent list of references and the index is satisfactory.

Gray's Anatomy

Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide "neuroprotection" in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-alpha, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-199908000-00001

Inflammatory mediators and stroke: new opportunities for novel therapeutics.

Inflammation and glial responses in ischemic brain lesions

Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in re...

Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels

Polymorphonuclear leukocytes have been implicated in the development of the "no-reflow" phenomenon after focal cerebral ischemia and reperfusion. To further understand the role of granulocytes in m...

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.25.1.202

P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion.

Ischemic cerebral injury is associated with activation of the blood coagulation cascade. To elucidate the contribution of fibrin formation to microvascular injury during focal cerebral ischemia and reperfusion, we have studied the time course and the localization of fibrin deposition in cerebral microvessels and the surrounding tissues during ischemia/reperfusion in a well-described nonhuman primate model.

Cerebral tissues from adolescent male baboons were examined after 2-hour middle cerebral artery occlusion (n = 3) and after 3 hours of middle cerebral artery occlusion and 1-hour (n = 6), 4-hour (n = 3), and 24-hour (n = 4) reperfusion; tissues from control primates (n = 3) also were examined. Fibrin deposition was detected by immunohistochemical techniques using the fibrin-specific monoclonal antibody MH-1. The number and size distribution of microvessels associated with fibrin were quantified by video-imaging microscopy.

Fibrin was associated with microvessels only in the ischemic zone where severe neuronal injury was documented, its frequency increasing with the reperfusion period (F4,26 = 3.80, P < .05). Extravascular fibrin deposition was significantly increased by 24-hour reperfusion compared with the other subjects (P < .05). Preischemia infusion of the anti-tissue factor monoclonal antibody TF9-6B4 resulted in significant reduction of intramicrovascular fibrin (P < .038 versus no intervention) at 1-hour reperfusion but had no effect on extravascular fibrin deposition.

These results suggest that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral ischemia/reperfusion and that exposure of focal cerebral ischemia/reperfusion and that exposure of plasma to perivascular tissue factor is partially responsible for occlusion formation. During ischemia the large plasma protein fibrinogen extravasates and interacts with parenchymal tissue factor, forming significant extravascular fibrin by 24 hours of reperfusion.

Fibrin contributes to microvascular obstructions and parenchymal changes during early focal cerebral ischemia and reperfusion.

The endothelial and smooth muscle integrin alphaVbeta3, a receptor for vitronectin and fibrinogen, participates in angiogenesis associated with wound healing and tumorigenicity. The microvascular expression of alphavbeta3 and fibrin during experimental middle cerebral artery occlusion and reperfusion in a nonhuman primate model was examined by computer-assisted video imaging microscopy. No microvascular expression of alphavbeta3 was seen in the control subjects (n = 3) or the non-ischemic basal ganglia of subjects undergoing 2-hour MCA:O (middle cerebral artery occlusion) or 3-hour occlusion with 1-hour (n = 3), 4-hour (n = 3), and 24-hour (n = 3) reperfusion. In the ischemic territory, alphavbeta3 appeared initially at 2 hours of middle cerebral artery occlusion. Up-regulation of alphavbeta3 was confined to the media of 30.0- to 50.0-micron-diameter arterioles in the ischemic core and correlated significantly with fibrin deposition in those vessels (P < 0.0005). Integrin alphavbeta3 and its ligand fibrinogen appear in a subpopulation of microvessels after focal cerebral ischemia.

Integrin alphavbeta3 is expressed in selected microvessels after focal cerebral ischemia.

Symptomatic intracerebral hemorrhage is an often-feared companion of acute cerebral ischemia treated with plasminogen activators. The pathophysiology of parenchymal hemorrhage is poorly understood and has been the subject of previous treatises in this series [1,2]. Clinical studies of this disorder suggest a spectrum of clinical severity from asymptomatic episodes diagnosed by computed tomographic (CT) scan or magnetic resonance imaging (MRI) to catastrophic events with debilitating or fatal issue [3–13]. The importance of understanding the pathogenesis of hemorrhagic events, particularly in the setting of fibrinolytic intervention, is emphasized by the dilemma that can arise in judging whether a particular hemorrhage may be reasonably attributable to the plasminogen activator the patient has received.

Mechanisms of Fibrinolysis-Associated Hemorrhagic Transformation

Recent studies have indicated that polymorphonuclear (PMN) leukocytes may contribute to the “no-reflow” phenomenon after focal cerebral ischemia and reperfusion by binding to the microvascular endothelium in the ischemic corpus striatum [1,2]. The nature of this interaction has been the subject of intense investigation [3]. Little is known about how the affected micro-vascular endothelia respond during focal cerebral ischemia and reperfusion. To understand the role of PMN leukocytes during reperfusion following middle cerebral artery ischemia, the responses of the endothelial cell adhesion receptors, in particular those related to PMN leukocytes, were examined.

Y. Okada

Papers

P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion.

Fibrin contributes to microvascular obstructions and parenchymal changes during early focal cerebral ischemia and reperfusion.

Integrin alphavbeta3 is expressed in selected microvessels after focal cerebral ischemia.

Mechanisms of Fibrinolysis-Associated Hemorrhagic Transformation

The Role of P-Selectin and ICAM-1 During Focal Brain Ischemia/Reperfusion