BACKGROUND. Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both beta-adrenergic receptor (betaAR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. METHODS: The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine betaAR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. RESULTS: After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol-stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol-stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. CONCLUSIONS: Persistent downregulation and desensitization of the lymphocyte betaAR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at-risk period after major surgery appears to be about 1 week or more.

Comment on Tissue injury in neutrophilic inflammation. [Inflamm Res. 1997]

An in vitro model was employed to study the potential role of streptococcal extra-cellular products, rich in streptolysin O, in cellular injury as related to streptococcal infections and post-streptococcal sequelae. Extra-cellular products (EXPA) rich in streptolysin O were isolated from type 4, group A hemolytic streptococci grown in a chemostat, in a synthetic medium. EXPA induced moderate cytopathogenic changes in monkey kidney epithelial cells and in rat heart cells pre-labeled with 3H-arachidonate. However very strong toxic effects were induced when EXP was combined with oxidants (glucose oxides generated H2O2, AAPH-induced peroxyl radical (ROO.), NO generated by sodium nitroprusside) and proteinases (plasmin, trypsin). Cell killing was distinctly synergistic in nature. Cell damage induced by the multi-component cocktails was strongly inhibited either by micromolar amounts of gamma globulin, and Evan's blue which neutralized SLO activity, by tetracycline, trasylol (aprotinin), epsilon amino caproic acid and by soybean trypsin inhibitor, all proteinase inhibitors as well as by a non-penetrating PLA2 inhibitor A. The results suggest that fasciitis, myositis and sepsis resulting from infections with hemolytic streptococci might be caused by a coordinated 'cross-talk' among microbial, leukocyte and additional host-derived pro-inflammatory agents. Since attempts to prolong lives of septic patients by the exclusive administration of single antagonists invariably failed, it is proposed that the administration of 'cocktails' of putative inhibitors against major pro-inflammatory agonizes generated in inflammation and infection might protect against the deleterious effects caused by the biochemical and pharmacological cascades which are known to be activated in sepsis.

I read with much interest the review article ‘‘Mechanisms of neutrophil-induced parenchymal cell injury’’(H. Jaeschke and C.W. Smith, J. Leukoc. Biol. 61, 647–653). As I read through the text it became apparent that very basic and relevant concepts as well as publications regarding the possible mecha- nisms by which phagocytes kill targets had not been included in the review. The authors rightfully write, ‘‘The question regarding the molecular mechanism of neutrophil-induced target cell injury is controversial.’’ Yet despite the common knowledge and understanding that the mechanisms of cell damage most probably involve an interaction among a multiplicity of agonists (a multicomponent system), the section, ‘‘Mechanisms of neutro- phil-induced parenchymal cell injury’’ had adopted an ex- tremely reductionist and oversimplified approach to the prob- lem. It considered (see Fig. 1) what seems to be the exclusive role of oxidants and proteinases as potential cell injuring agents, as if these are the sole noxious agents generated by activated phagocytes. Although I fully respect the prerogatives and choices by the authors to refer exclusively to hepatocytes and parenchymal cells and to select citations from the literature pertaining to these tissues in order to support their thesis, it is still intriguing why not a single word was mentioned about the obvious possibility that oxidants, proteinases, and additional agonists might perhaps act mainly in concert (synergize) to injure any cell type? To the best of our knowledge and experience in this field of research (see list of recommended literature), even a normal cell line, as well as some of the tumor cells tested in vitro by us and by others, which could not readily be killed by physiologi- cal amounts of oxidants (H2O2 ROO, HCIO, NO) alone, were nevertheless rapidly killed in a synergistic manner if the oxidants were combined with any of a long list of membrane- perforating agents. These included phospholipase A2, phospho- lipase C, lysophosphatides, fatty acids, microbial hemolysins, cationic peptides and proteins, bile salts, complement compo- nents, and xenobiotics such as ethanol, methanol, and lindane. The inclusion of proteinases (trypsin, plasmin, elastase chymotrypsin), together with oxidants and the membrane perforators, further significantly enhanced cellular damage. It is also of great interest and is perhaps paradoxical that microbial agents might also synergize with phagocyte-derived agonists, but in an adverse fashion, to injure host tissues. It is also important to consider that all these proinflammatory agonists might be simultaneously present in infectious and inflammatory sites. Our studies also suggested that the induction of a sublethal membrane injury abolished, to a large extent, the potent antioxidant defenses of the cells— a finding of great significance. The readers of the Journal of Leukocyte Biology might be interested in a series of publications dealing with the ‘‘syner- gism’’ concept of cellular injury as related to infectious and inflammatory conditions, which have been published since 1986 (see list of recommended literature). An invited overview by Ginsburg and Kohen [8] undertook to discuss, in great detail, those papers that described the role of synergism in cellular injury. Unfortunately and enigmatically, publications that have described the ‘‘synergism concept’’ of cellular injury published since 1986 are hardly ever cited. If the synergism concept of cellular injury is logical and conforms with the current knowledge in the field, publications describing this phenom- enon should be quoted. If on the other hand these ideas are extreme, bizarre, and scientifically unacceptable, such papers should be discussed and challenged properly and even ridi- culed. However, it is totally unacceptable that such publica- tions be simply ignored. Approaching the third millennium, the readers of scientific journals deserve not an oversimplified approach to complicated scientific issues, but more realistic, integrated, and updated appraisals of the literature even if these might not always fully conform with the investigator’s own concepts or with the prevailing paradoxes, dogmas, cliches, and myths. It is also very surprising, and of great concern, why the referees of the papers did not bring any of these publications and concepts to the attention of the authors. After all, the main task of the referees and the editorial board is to criticize the validity and novelty of investigations brought to their attention and to strongly instruct negligent authors to give proper credit to relevant papers and concepts in their field of research. It is regrettable that this has not happened. Unfortunately, this is how, for the sake of brevity and a reductionist approach to the solution of complex biological phenomena, very basic and pioneering investigations and ‘‘novel’’ concepts may be simply ignored and buried for good. It is obvious that the ones who might suffer most from such an approach to the compilation of reviews and papers are the investigators, the readers, and perhaps most importantly, the credibility of journals at large. I shall greatly appreciate receiving comments and sugges- tions about these matters.

The mechanisms of cellular damage caused by infectious and inflammatory processes are complex and are still not fully understood. There is, however, a consensus that reactive oxygen species (ROS) generated by phagocytes migrating to injured tissues might be the main agents responsible for cellular damage in inflammatory processes. However, because both activated phagocytes and catalase-negative, peroxide-producing, toxigenic bacteria (Streptococci, Clostridiae) secrete a near-identical array of proinflammatory agonists, including reactive oxygen species (ROS), and because these microbial species might kill their targets by a synergism among several of their secreted enzymes (a multicomponent system), we postulated that activated phagocytes might also function in the same way. Using radiolabeled targets, in culture, we demonstrated that subtoxic amounts of a variety of oxidants (H2O2, radicals produced by xanthine-xanthine-oxidase, peroxyl radical, NO) acted synergistically with subtoxic amounts of a large series of membrane-perforating agents (microbial hemolysins, phospholipases, fatty acids, cationic proteins, proteinases, bile salts, the attack complex of complement, the xenobiotics, lindane, ethanol, methanol) to kill cells in culture and to release large amounts of arachidonic acid and metabolites. Membrane perforators might act primarily to overcome the potent antioxidant systems present in all mammalian cells and scavengers of ROS and inhibitors of the additional agonists might act to abolish the synergism among ROS and the membrane-damaging agents. It is also proposed that protection against tissue damage in vivo should also include 'cocktails' of appropriate antagonists. It is enigmatic that those publications which do describe both in-vitro and in-vivo models proposing that a synergism among a multiplicity of agonists might truly represent the mechanisms by which tissues are injured, in vivo, are hardly ever quoted in the current literature.