Abstract:

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.