Abstract:

Comment on Proteolytic enzymes and airway diseases. [Eur Respir J. 1998] Neutrophil serine proteinases and defensins in chronic obstructive pulmonary disease: effects on pulmonary epithelium. [Eur Respir J. 1998] To the Editor: I have recently read with much interest two excellent reports in the European Respiratory Journal which discussed the role of neutrophil proteinases and defensins in chronic obstructive pulmonary disease [1] and in airway diseases [2]. Reading through these articles, it was surprising not to find any considerations of a major aspect related to the elucidation of the possible mechanisms of tissue damage in the lungs during inflammation. I refer to extensive studies from several laboratories which had proposed that tissue damage in inflammatory and infectious processes may primarily be the result of a synergistic "cross talk" among a multiplicity of pro-inflammatory agents (a multi-component system) [3, 4]. A series of publications [5±14] have shown that a severe and rapid membrane injury (necrosis) could be initiated in mammalian cells by a synergism among subtoxic concen- trations of three major groups of agonists. These included a) oxidants (H2O2, peroxyl radical, oxidants generated by xanthine-xanthine-oxidase, NO, HOCl, OONO-), b) mem- brane -perforating agents (microbial haemolysins/phospho- lipases A2 and C, lysophosphatides, free fatty acids, cationic proteins, histone [9] and defensins [5], and c) highly cationic proteolytic enzymes, (elastase, cathepsin G) [3, 4, 12]. These synergistic cytotoxic effects can be further amplified by certain cytokines. Furthermore, combinations of oxidants and elastase have also been shown to synergize to cause severe lung damage in animal models [6±10]. It has also been proposed that a deleterious synergism among microbial and host-derived pro-inflammatory agonists may frequently contribute to tissue injury in many infectious and post- infection complications [3, 4]. A notable example is, sepsis and the "flesh-eating" syndrome caused by highly toxigenic and invasive bacteria. Other studies had also shown that subtoxic amounts of the membrane-active xenobiotics, ethanol, methanol, n-butanol and the pesticide linden [13], could also synergize with subtoxic concentrations of peroxide, proteinases and cationic agents to amplify the damage to endothelial cells in culture. The results with the xenobiotics are of especial interest and concern to pulmonologists as these volatile agents may be inhaled and might then synergize with oxidants, proteinases and cationic proteins released either by accumulating neu- trophils or by activated lung macrophages to cause damage to both epithelial and endothelial cells. It has also been documented that ˜-lactam antibiotics and a large variety of cationic agents including, elastase, cath- epsin G, defensins, lysozyme, myeloperoxidase, spermine, spermidine, histones, polymyxin B and chlorhexidine are all capable of activating the autolytic wall enzymes (murami- dases) in bacteria leading to bacteriolysis [14]. Bacteriolysis at least in Gram-positive bacteria induced either by ˜- lactams or by cationic agents can, however, be strongly inhibited by sulphated polyanions presumably by inactivat- ing the autolytic wall enzymes responsible for breaking down the rigid cell wall. It is accepted that the massive release widely of bacterial wall components (lipopolysac- charide, lipoteichoic acid (LTA), peptidoglycan), in vivo, can activate macrophages to release cytotoxic cytokines, NO and also to activate the complement and coagulation cascades leading to sepsis, systemic inflammatory response syndrome (SIRS), multiple organ disfunction syndrome (MODS) and multiple organ failure (MOF) [15]. Today there are controversial opinions and hot debates regarding the approaches to treat sepsis, adult respiratory distress syndrome (ARDS) and additional post-infectious and inflammatory sequelae [15]. Unfortunately, the exclu- sive use of single antagonists to treat these syndromes has yielded poor results. Such failures may principally be due to, a) the lack of adequate and rapid tests to predict the onset of such complications so that treatment of patients usually starts too late, and b) a lack of sufficient awareness that fighting the deleterious effects caused by synergistic cytotoxic mechan- isms necessitates the use not of single antagonists but of cocktails comprised of a multiplicity of anti-inflammatory agents. Hopefully, a wider recognition of synergism concept of cellular injury [3, 4, 11±13] might offer a new and more realistic approach to this complex and still unsolved clinical problem. I. Ginsburg Dept of Oral Biology, Hebrew University - Hadassah Faculty of Dental Medicine, Jerusalem, Israel. Fax: 972 26758583.