Temporal relation between neutrophil accumulation and myocardial reperfusion injury

Abstracts From the Literature-Physiology Selected

by David

Tumor Necrosis Factor and the Acute Metabolic Response to Tissue Injury in Man. Starnes HF Jr, Warren RS,

Jeevanandam

M, et al.

R. Dantzker Role of Xanthine Oxidase fleperfusion Injury. Granger

ture and Intestinal LaMont

Toxin

A Perturbs

Cytoskeletal

Struc-

Tight Junction Permeability of Cultured Human Epithelial Monolayers. Hecht G, Pothoulakis C,

JT, et al.

J Clin Invest 82:1516, 1988.

Toxin A of Clostridium dificile causes severe inflammatory enterocolitis in man and animals that appears to be mediated in part by acute inflammatory cells that migrate into the toxin A-exposed mucosa. To determine the direct effects of toxin A on intestinal epithelial permeability and structure in the absence of other modulating factors, we used cultured monolayers of a human intestinal epithelial cell line (T,,). A toxin A concentration of 7 x 10-l fig/ml (3 x 10w9M) nearly abolished monolayer transepithelial resistance within 6-8 h. This marked permeability defect occurred while the monolayers were still confluent. Dual sodium-mannitol flux studies localized the permeability defect to the intercellular tight junction. Cytotoxicity assays and morphological evaluation using Nomarski optics and electron microscopy failed to demonstrate any evidence of cell damage at the time the maximum resistance response was observed. Fluorescent staining for F actin, however, revealed a marked decrease in fluorescent intensity in toxintreated monolayers versus controls. These data show that toxin A can directly affect the barrier function of this model intestinal epithelium and initially does so by selectively enhancing tight junction permeability. Furthermore, cytoskeletal structure is markedly altered over the same time course, although the integrity of individual cells is maintained. Because the cytoskeleton of intestinal epithelial cells is known to be capable of regulating tight junction permeability, we speculate that the above effects of toxin A on epithelial barrier function result from alterations of the cytoskeleton. (Reprinted with permission.) Journal

of Critical

Care, Vol4,

No 3 (September),

1989:

in Ischemia-

Am J Physiol 255Hl269,

In this lecture, evidence is presented to support the following hypothesis regarding the roles of xanthine oxidasederived oxidants and granulocytes in ischemia-reperfusioninduced microvascular injury. During the ischemic period, ATP is catabolized to yield hypoxanthine. The hypoxic stress also triggers the conversion of NAD-reducing xanthine dehydrogenase to the oxygen radical-producing xanthine oxidase. During reperfusion, molecular oxygen is reintroduced into the tissue where it reacts with hypoxanthine and xanthine oxidase to produce a burst of superoxide anion and hydrogen peroxide. In the presence of iron, superoxide anion and hydrogen peroxide react via the Haber-Weiss reaction to form hydroxyl radicals. This highly reactive and cytotoxic radical then initiates lipid peroxidation of cell membrane components and the subsequent release of substances that attract, activate, and promote the adherence of granulocytes to microvascular endothelium. The adherent granulocytes then cause further endothelial cell injury via the release of superoxide and various proteases. (Reprinted with permission.) Temporal

difici/e

Granulocytes

DN.

1988.

J Clin Invest 82:1321,1988.

Tumor necrosis factor (cachectin), a protein produced by monocytes and macrophages, has been implicated as an important mediator of the lethal effects of endotoxic shock and the cachexia of chronic infection. Recombinant human tumor necrosis factor (Y (rTNF) was given intravenously to patients as part of an antineoplastic trial. Fever, tachycardia, and at higher doses, hypotension occurred after a single injection of rTNF. Metabolic effects after rTNF administration were dose related and included enhanced energy expenditure with elevated CO, production, increased whole body protein metabolism and peripheral amino acid efflux from the forearm, and decreased total arterial amino acid levels associated with a significant increase in plasma cortisol. Elevated serum triglycerides, as well as increased glycerol and free fatty acid turnover were seen, suggesting increased whole body lipolysis and fat utilization after rTNF. These findings indicate that administration of TNF in man reproduces many of the acute physiologic and metabolic responses to tissue injury, including energy substrate mobilization (Reprinted with permission.) Clostridium

and

pp 225-238

Myocardial

Bugelski,

Relation

Between

Reperfusion

PJ, et al.

Neutrophil

Injury.

Smith

Accumulation

EF

Am J Physiol255:H1060,

and

ZZZ, Egan

JW,

1988.

Infiltration of polymorphonuclear leukocytes (PMN) is associated with the progression of myocardial infarction and reperfusion injury. However, little is known about the time course of cellular infiltration. To investigate this issue, rats were subjected to 30 min of coronary artery occlusion followed by reperfusion for ~96 h. Myocardial injury was determined by measuring the depletion of myocardial creatine phosphokinase activity, and PMN infiltration was assessed by measuring myeloperoxidase (MPO) activity. MPO activity increased from 0.7 U/g tissue in non-operated animals, to a peak of 6.7 + 0.8 and 6.4 + 1.4 U/g at 6 and 24 h after coronary artery reperfusion, respectively. MPO activity decreased to 3.3 f 0.8 U/g at 48 h and 1.1 + 0.4 U/g at 96 h, suggesting diminished PMN accumulation. Histological examination confirmed the accumulation and resolution of PMN over the 96-h period. At 24 h, there was a signifficant linear correlation between infarct size and MPO act,ivity, whereas at 96 h no relationship was found. These data indicate that PMN infiltration occurs early in response to reperfusion injury and persists for only 24 h after initiation of reperfusion. These findings suggest that attempts to moderate inflammatory cell responses to myocardial injury should be administered early after coronary artery reperfusion to limit the accumulation of potentially deleterious inflammatory cells. (Reprinted with permission.) Ischemia-Induced and reperfusion-Induced Importance of Heart Rate. Bernier M,

DJ.

Am J Physiol256:H21,

Arrhythmias:

Curtis

MJ.

Hearse

1989.

The relationship between heart rate and ischemia-induced and reperfusion-induced arrhythmias was studied using 573 225