Biomedical subjects
W B WOOD
Publications and source records attributed to W B WOOD.
Studies on the pathogenesis of fever. VII. Preliminary chemical characterization of leucocytic pyrogen.
Study of the chemical properties of the pyrogenic component of rabbit polymorphonuclear leucocytes reveals it to contain an essential, non-dialyzable protein which: (a) is precipitated by perchloric acid, (b) is removed by extraction with phenol, (c) is soluble in 50 per cent methanol and 33 per cent saturated ammonium sulfate, and (d) is destroyed by the proteolytic action of both trypsin and pepsin. By combined chemical and chromatographic techniques the leucocytic pyrogen has been purified approximately 50-fold. The partially purified material contains less than 1 per cent carbohydrate, is resistant to periodate oxidation, is unaffected by extraction with butanol and contains at least two immunologically active components when tested by the Ouchterlony gel-diffusion technique. Its chemical properties distinguish it from other known pyrogenic substances which have been implicated in the pathogenesis of fever.
Phagocytosis, with particular reference to encapsulated bacteria.
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Studies on the pathogenesis of fever. VI. The interaction of leucocytes and endotoxin in vitro.
Study in vitro of the interaction of bacterial endotoxin with rabbit polymorphonuclear leucocytes has resulted in the following findings: 1. Incubation of endotoxin and leucocytes in saline results in: (a) the release of leucocytic pyrogen, and (b) the inactivation of endotoxin. 2. Cell-free extracts of leucocytes also inactivate endotoxin. 3. Incubation of leucocytes in "physiological" saline causes rapid discharge of leucocytic pyrogen. In contrast, relatively little pyrogen is released by leucocytes incubated in fresh serum. 4. The release of leucocytic pyrogen in serum is markedly stimulated by the presence of endotoxin. 5. Leucocytes obtained from tolerant rabbits interact with endotoxin in essentially the same manner as leucocytes from normal rabbits. The pertinence of these findings to the pathogenesis of fever and to related information concerning human leucocytes has been discussed.
Studies on the pathogenicity of group A Streptococci. I. Its relation to surface phagocytosis.
Four strains of Group A streptococci, possessing different degrees of virulence for both mice and rats, were tested for susceptibility to phagocytosis on glass slides, in glass roller tubes, and on the surfaces of freshly excised tissues and moistened filter paper. All of the tests were performed in the absence of serum to exclude the possible presence of opsonins. Only under conditions which allowed surface phagocytosis to take place was there a correlation between virulence and susceptibility to phagocytosis. A similar relationship between virulence and surface phagocytosis was also demonstrable in vivo during the early stages of experimental streptococcal peritonitis. Systematic study of the evolution of the peritonitis revealed that its outcome was determined by the phagocytic reaction which occurred in the first few hours of the infection.
Studies on the pathogenicity of group A streptococci. II. The antiphagocytic effects of the M protein and the capsular gel.
A QUANTITATIVE STUDY OF THE COMBINED ANTIPHAGOCYTIC EFFECTS OF THE M PROTEIN AND THE HYALURONIC ACID CAPSULES OF FOUR STRAINS OF GROUP A STREPTOCOCCI REVEALED THE FOLLOWING FACTS RELATING TO THEIR INTRAPERITONEAL VIRULENCE IN MICE AND RATS: 1. The most virulent strain, S23M (matt), produced both a large hyaluronic acid capsule and a full complement of M protein, the combined effects of which rendered the organism highly resistant to surface phagocytosis. 2. The slightly less virulent strain, T14/46 (matt virulent) was somewhat more susceptible to surface phagocytosis owing to the fact that its smaller capsule was less antiphagocytic than that of the S23M organism. 3. The glossy variant of the S23 strain (S23G), which ranked third in virulence, was still more susceptible to surface phagocytosis because of its lack of detectable M substance. Its large hyaluronic acid capsule, however, was capable of protecting it against phagocytosis on glass. 4. The least virulent strain, T14 (matt avirulent), was the most susceptible of all to phagocytosis. Though it possessed both M substance and capsule, which together prevented its phagocytosis on glass, each of them was shown to be quantitatively and functionally deficient as compared to Strain S23M. The differences in phagocytability, which appear to be directly related to the pathogenicity of the organisms, could be adequately demonstrated in vitro only by phagocytic tests designed to measure surface phagocytosis in the absence of opsonins. This fact is in keeping with the observation, previously reported, that surface phagocytosis plays a critical role in the defense of the host, particularly during the earliest stages of experimental streptococcal infections. Its possible relation to suppuration during the later stages of infection is also discussed.
The role of endogenous pyrogen in the genesis of fever.
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Studies on the pathogenesis of fever. III. The leucocytic origin of endogenous pyrogen in acute inflammatory exudates.
The evolution of an acute inflammatory exudate produced in rabbits by the intraperitoneal injection of saline has been described. Evidence has been presented that polymorphonuclear leucocytes release endogenous pyrogen into the cell-free fluid of the exudate. Leucocytes from such exudates have also been shown to release pyrogen into the surrounding medium during incubation in vitro at 37 degrees C. The results of parallel cytological studies have provided evidence which suggests that the leucocytes give up their pyrogen while functionally intact. These observations add further support to the hypothesis that polymorphonuclear leucocytes play a significant role in the pathogenesis of fever.
Studies on the pathogenesis of fever. IV. The site of action of leucocytic and circulating endogenous pyrogen.
By means of a method designed to compare the febrile responses produced by intracarotid and intravenous injections, the endogenous pyrogen, which is contained in leucocytic exudates and is present in the serum of rabbits 2 hours after intravenous injections of typhoid vaccine, has been shown to act directly upon the thermoregulatory centers of the brain. In contrast, the exogenous bacterial pyrogen present in serum obtained 5 minutes after vaccine injections was found to act by a different and less direct mechanism. These observations add strong support to the original hypothesis that endogenous pyrogen, presumably derived from polymorphonuclear leucocytes, is an essential factor in the pathogenesis of endotoxin fever.
Studies on the pathogenesis of fever. V. The relation of circulating endogenous pyrogen to the fever of acute bacterial infections.
An endogenous pyrogen, which is indistinguishable from leucocytic pyrogen, has been demonstrated in the blood streams of rabbits with fevers caused by experimental pneumococcal and streptococcal infections. Like the endogenous pyrogen previously detected in the serum of animals with fever produced by the intravenous injection of typhoid vaccine, the newly discovered circulating factor acts directly upon the thermoregulatory centers of the brain. Its origin from polymorphonuclear leucocytes at the site of infection appears to have been established. The possible relationship of this circulating endogenous pyrogen to the pathogenesis of other forms of fever is discussed.
Surface phagocytosis; further evidence of its destructive action upon fully encapsulated pneumococci in the absence of type-specific antibody.
Experiments recently reported (18) have been interpreted to indicate that surface phagocytosis plays no significant part in natural antipneumococcal defense. A repetition of these experiments has revealed: (a) that the cellular content of the leucocytic suspensions used in the phagocytic tests was of a different order of magnitude from that of the exudates which usually exist in infected tissues, (b) that the suspensions were too dilute to allow surface phagocytosis of pneumococci to occur, and (c) that the ratio of bacteria to leucocytes. was such that, when a sufficiently concentrated exudate was employed, the pneumococci injured the leucocytes and thus prevented phagocytosis from taking place. When conditions of the tests were suitably controlled, and conventional quantitative methods were employed to measure the end results of the phagocytic reaction, the essential observations relating to surface phagocytosis were fully confirmed. The significance of this non-antibody mechanism of defense in pneumococcal infections was thus further substantiated.
The underlying cause of unrest in university medicine.
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Tracheal constriction in the dog.
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An experimental analysis of the curative action of penicillin in acute bacterial infections. I. The relationship of bacterial growth rates to the antimicrobial effect of penicillin.
Three strains of pneumococcus (types I and III), equally sensitive to penicillin, have been shown to be killed by the antibiotic in vitro when grown either in enriched beef infusion broth or in a thin serous exudate. Killing of the bacteria resulted promptly when the penicillin was added during the logarithmic phase of growth but failed to occur if addition of the antibiotic was delayed until the later "stationary" growth phase. In analogous experiments with thick purulent exudates from established subcutaneous abscesses, the pneumococci failed to grow rapidly, and added penicillin exerted only a relatively slow bactericidal effect. The relevance of these in vitro observations to the curative action of penicillin was demonstrated in a systematic histologic study of the antimicrobial effect of the drug in experimental (type I) pneumococcal pneumonia. Evidence was obtained that at least two distinct processes are involved. The first, the direct bactericidal effect of the penicillin itself, was shown to operate in the outer edema zone of the spreading pneumonic lesion where the micro-organisms multiply rapidly in the thin serous exudate. The second, which predominates in the older more central portions of the lesion, was demonstrated to depend upon destruction of the pneumococci by phagocytosis. Here the bacteria, having presumably reached a relatively stationary phase of growth in the alveolar exudate, are resistant to the bactericidal action of the penicillin but are readily destroyed by the phagocytes.
An experimental analysis of the curative action of penicillin in acute bacterial infections. II. The role of phagocytic cells in the process of recovery.
Type I pneumococci injected into the leg muscles of otherwise normal mice reached a maximum total population of approximately 10(6) organisms. In mice rendered severely leucopenic by previous irradiation the maximum bacterial counts recorded were of the order of 10(9). Since the lesions in the latter animals were relatively acellular, the thousandfold difference in the two experiments represented a rough measure of the antibacterial action of the leucocytic exudate. The suppressive effect of the leucocytic exudate was shown by histologie studies to involve phagocytosis. The ingestion of pneumococci was clearly demonstrable within the first 12 to 18 hours. Accordingly, it was attributed to surface phagocytosis. In support of this conclusion was the finding that type III pneumococci reached a significantly higher total population in the myositis lesions than did type I. The type III strain used had been previously shown to be resistant to surface phagocytosis during active growth, whereas the type I strain was known to be susceptible throughout its growth phase. Evidence was also presented that the dense leucocytic exudate probably caused in addition a significant degree of bacteriostasis. When penicillin therapy was begun 9 hours after inoculation, the pneumococci were cleared from the lesions with equal rapidity regardless of the presence or absence of leucocytic exudate. At this early stage the pneumococci were multiplying rapidly in the lesions of both the irradiated and unirradiated mice and therefore were promptly killed by the direct action of the penicillin. When the start of treatment was delayed, however, until 24 hours after inoculation, the bacteria in both sets of lesions had already reached their maximum counts and therefore were presumably resistant to the bactericidal effect of the antibiotic. Under such circumstances the destruction of the bacteria was found to be significantly less prompt in the acellular lesions than in those with a normal cellular exudate. It is concluded from these findings that, in established pneumococcal myositis in mice, the curative effect of penicillin is due, not to the bactericidal action of the antibiotic alone, but rather to the combined effect of the drug and the cellular defenses of the host. The same conclusion also appears to be applicable to analogous acute infections in man, particularly when they are sufficiently advanced to be definitively diagnosed.
An experimental analysis of the curative action of penicillin in acute bacterial infections. III. The effect of suppuration upon the antibacterial action of the drug.
The results of the experimental analysis reported in this and the two preceding papers (10, 11) indicate that in murine pneumococcal infections penicillin per se destroys the invading organisms only in those parts of the lesions where the bacteria are multiplying rapidly and are thus maximally susceptible to the bactericidal action of the drug. In areas where the bacterial growth rate is slowed, either because the pneumococci have reached a maximum population density, or because the accumulated exudate affords a relatively poor medium for rapid growth, the destructive effect of the antibiotic is greatly diminished. In such portions of the lessions the cellular defenses of the host are observed to play a major role in eliminating the bacteria. In sites where frank suppuration has developed, however, even the combined actions of the penicillin and the cellular defenses of the host are relatively ineffective in ridding the tissues of bacteria. Here, because of the poor medium provided by the pus, the pneumococci remain metabolically sluggish and therefore are not killed rapidly by the penicillin. At the same time the leucocytes in the necrotic exudate have deteriorated to the point where they cannot effectively perform their phagocytic functions. As a result, bacteria persist in such lesions for many days in spite of the most intensive penicillin treatment administered both locally and systemically. A strict analogy cannot be drawn between the action of penicillin upon specific pneumococcal lesions produced in the laboratory and its effect upon acute bacterial infections in man. Host-parasite relationships in acute bacterial infections are determined not only by the strain of parasite and the specific host involved, but also by the site in the body at which the infection occurs (16). Nevertheless, in spite of the number of variables involved, it may be possible, by means of selected laboratory models, to illustrate general principles of infection which in all probability apply to human disease. Bearing in mind the limitations of the methods employed in the present experiments, it would appear justifiable to draw the following conclusions concerning the clinical use of penicillin in acute infections caused by penicillin-sensitive bacteria. The earlier that treatment is begun the more likely is penicillin to effectuate a rapid cure. When therapy is started before the bacteria have reached a maximum population density in any part of the lesion, and before a cellular exudate is formed, the great majority of the infecting organisms will be in a state of active multiplication and thus will be killed promptiy by the bactericidal action of the drug. If, on the other hand, treatment is delayed until the bacterial growth has attained its maximum in older parts of the lesion, and the inflammatory reaction has become well advanced, the resultant slowing of bacterial metabolism will so interfere with the bactericidal action of the penicillin that ultimate destruction of many of the bacteria will have to depend upon the slower clearing effect of the phagocytic cells. In such instances of delayed therapy specific antibody, which is formed relatively slowly, may play an important role in recovery (6). If relapse is to be avoided, however, penicillin therapy must often be continued longer in well established infections than in those treated at a very early stage. Still further delay in treating infections which are prone to cause tissue destruction and suppuration, may lead to the establishment of abscesses. Fully developed abscesses often will not respond to chemotherapy alone; they will ultimately require drainage. As shown by the present murine experiments, the relative ineffectiveness of penicillin under these circumstances is due not only to the failure of the drug to kill the metabolically sluggish bacteria surviving in the pus, but also to the ineffectiveness of the phagocytic cells, most of which are non-motile or dead. Even if specific antibody gains access to such purulent foci, many of the bacteria will continue to survive because of the degenerated state of the leucocytes. It is evident, therefore, that the stage of the infection at which penicillin treatment is begun is often crucial. Equally critical may be the location of the infection. Bacterial lesions in different sites of the body vary greatly in their responses to penicillin therapy. This inconstancy of therapeutic effectiveness is due primarily to the participation of host factors of defense which differ widely in various tissues and at the same time play a major role in the curative action of the antibiotic. In cases of pneumococcal pneumonia, for example, in which each milliliter of the patient's blood contains more than 1000 pneumococci, blood cultures may become negative in a matter of minutes after the start of intensive treatment (17). The remarkable promptness with which penicillin therapy controls such acute bacteriemia is due, first, to its suppressive effect upon the primary infection in the lungs and regional lymph nodes from which the bacteria are being poured into the blood stream (16) and, secondly, to its synergistic action with the cellular defenses of the circulation. The latter are known to be extraordinarily efficient, perhaps more so than in any other tissue of the body (18). Assisting them in destroying the circulating bacteria is the penicillin's own bactericidal effect, which operates rapidly upon the metabolically active organisms in the plasma. Rarely, if ever, as they often do in other tissues of the body (10), do bacteria in the bloodstream reach such numbers, or do inflammatory cells accumulate intravascularly to such an extent, as to create metabolic conditions which depress the bactericidal actions of the antibiotic. In contrast, more prolonged and extensive penicillin therapy is needed to cure pneumococcal endocarditis (19), meningitis (19, 20), or infections of the serous cavities (3, 4). The cellular defenses of the heart valves and of the "open" fluid-containing cavities of the body are relatively inefficient as compared to those that operate in the bloodstream and in tissues with tightiy knit architectures such as the lungs and lymph nodes (16). In endocarditis relatively few phagocytic cells ever reach the site of the offending bacteria (21), and in infections of fluid-containing cavities, the phagocytic efficiency of the mobilized leucocytes is seriously interfered with by the "dilution effect" of the fluid (22, 23). Accordingly, final destruction of the bacteria must depend primarily upon the bactericidal effect of the antibiotic itself, since little assistance is provided by phagocytosis. It is no wonder, therefore, that such infections, as compared to bacteriemia, are relatively refractory to penicillin therapy. Certainly penicillin, in spite of its remarkable therapeutic properties, falls far short of being a therapia sterilans magna (24). Its effectiveness does not depend solely upon the inherent susceptibility of the infecting agent to its antimicrobial action. How readily it will cure a given infection is determined also by the state of growth of the bacteria in the various zones of the lesions, the influence of the purulent exudate upon the bactericidal action of the drug, and the destructive effect of the inflammatory phagocytes upon the invading bacteria. Optimal use of penicillin as a therapeutic agent requires due consideration of all of these factors. Finally, it should be emphasized that the conclusions drawn from this experimental analysis cannot be applied to antibiotic therapy in general. They pertain only to the action of penicillin in acute infections caused by penicillin-sensitive bacteria which act in the host as extracellular parasites (16). The most common human infections included in this category are those caused by pneumococci and Group A beta hemolytic streptococci.(7) Whether they apply also to infections due to penicillin-sensitive staphylococci may be questioned because of recent evidence that certain pathogenic strains will survive phagocytosis (27). In diseases such as tuberculosis, brucellosis, and typhoid fever, which are treated with antibiotics having properties different from those of penicillin (28) and which are caused by bacteria capable of intracellular parasitism (28), factors other than those considered in the present analysis must certainly be involved in the curative effect of antimicrobial therapy.
Studies on the anti-inflammatory effects of cortisone.
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