Gareth M. Green

Antibacterial mechanisms of the urinary bladder

THE DISAPPEARANCE OF BACTERIA FROM THE NORMAL URINARY BLADDER IS APPARENTLY A FUNCTION OF TWO HOST DEFENSE MECHANISMS: the mechanical clearance of organisms by voiding, and the antibacterial activity of the bladder wall. This study quantified the relative contribution of each of these mechanisms to the resistance of the bladder to bacterial infection.(32)Phosphorus-labeled E. coli. S. aureus, and P. mirabilis were each injected into the urinary bladders of unanesthetized female guinea pigs. At intervals after voiding, the bladders were removed, washed, homogenized, and assayed for residual radioactivity and viable bacteria. Mechanical clearance was measured by the changes in total radioactive count. Antibacterial activity was quantified by comparing the bacterial to radioactive ratios of the original bacterial inoculum with similar ratios in the bladder homogenates. More than 99.9% of the bladder inoculum was rapidly excreted and about 0.1% (10(4)-10(5)) organisms remained attached to the bladder wall. Of those E. coli attached to the bladder, rapid sequential reduction in viability occurred and reached a level of 85% loss at 30 min after inoculation. 4 hr after challenge, less than 10% of those organisms still attached to the bladder mucosa remained viable. P. mirabilis was handled with equal facility, but S. aureus showed a reduction in viability of only 46% at 1 hr and 67% at 4 hr after inoculation. 6 hr after infection with S. aureus, 6 of 12 guinea pig bladders showed multiplication of the organisms still attached to the bladder wall; only 1 of 12 animals challenged with E. coli had comparable multiplication. The mechanism whereby the bladder wall kills bacteria is unclear, but it did not appear to be related to an antibacterial activity of urine, clumping of organisms on bladder mucosa, phagocytosis by leukocytes, or serum levels of bactericidal antibody. Although it is clear that the bladder exhibits intrinsic antibacterial properties, the role of this defense mechanism in the pathogenesis of urinary tract infection requires further clarification.

The effect of Sendai virus infection on bactericidal and transport mechanisms of the murine lung

Pulmonary virus infections predispose to bacterial infections in the lung. The mechanism of this effect was studied by quantitative comparison of the effects of airborne acute viral infection on pulmonary transport vs. in situ bactericidal mechanisms in mice. Animals infected by aerosol with 10(4) TCID(50) of Sendai virus developed pathologic pulmonary changes of interstitial pneumonitis, bronchial epithelial desquamation, and peribronchial mononuclear cell infiltration 7 days later. At that time, the mice were challenged with an aerosol of viable (32)P-labeled Staphylococcus aureus. Pulmonary bactericidal activity and physical transport by the lung were determined by the determination of viable staphylococcal and (32)P radiotracer counts respectively at 4, 24, 48, and 72 hr after bacterial challenge. Infected mice showed a significant decrease from normal in the rate of reduction of viable bacterial counts in the first 4 hr after challenge followed by a proliferation of the staphylococci. By contrast, radiotracer removal rates at 4 and 24 hr were similar in infected and noninfected mice. There was a small but significant retention of (32)P in the lungs of the infected animals at the later periods. These data demonstrate that bacterial multiplication associated with virus infection of lungs is related to defects in in situ bactericidal (phagocytic) mechanisms rather than transport mechanisms of the lung, despite histologic evidence of extensive destruction of bronchial-ciliated epithelium.

Defect in intracellular killing of Staphylococcus aureus within alveolar macrophages in Sendai virus-infected murine lungs.

Bacterial multiplication associated with virus infections is related to defects in in situ bactericidal (phagocytic) mechanisms of the lung. To determine whether the phagocytic defect was in bacterial ingestion and/or intracellular digestion, mice were infected with a sublethal dose of aerosolized Sendai virus and challenged 7 days later with a finely dispersed aerosol of Staphylococcus aureus. Groups of uninfected and virus-infected mice were sacrificed at 0, 6, 12, and 24 h after challenge, the lungs were perfused with formalin in situ, and the intra- or extracellular location of the bacteria was determined histologically. At 0 h, 49% and 51% of the staphylococci had an intracellular location in virus and nonvirus-infected lungs, respectively. With time, decreasing numbers of staphylococci were observed within the phagocytic cells of nonvirus-infected lungs, mostly as single organisms or in small clusters of less than four. In contrast, in focal area of virus-infected lungs, increasing numbers of phagocytic cells showed clumps of more than 25 bacteria/cell. These data demonstrate that virus-infected suppression of pulmonary antibacterial activity against S. aureus is related primarily to defects in intracellular processing mechanisms.

Cigarette smoke—A proposed metabolic lesion in alveolar macrophages

Abstract The effects of the filtered gas phase of cigarette smoke were investigated with respect to certain enzyme activities of rabbit alveolar macrophages. Preliminary experiments with crystalline preparations of glyceraldehyde 3-phosphate dehydrogenase showed that cigarette smoke is a potent inhibitor of this enzyme and that protection from inhibition by smoke is afforded by cysteine. Other experiments, in which enzyme activity was measured in alveolar macrophages, demonstrated inhibition of glyceraldehyde 3-phosphate dehydrogenase activity in cells treated with cigarette smoke and protection by cysteine. There was no significant impairment of the activities of glucose 6-phosphate dehydrogenase and lactic dehydrogenase in smoke-treated macrophages. Histochemical evidence supported these findings. It is suggested that a relationship exists between loss of alveolar macrophage phagocytic competence and inhibition of glyceraldehyde 3-phosphate dehydrogenase. This paper discusses impaired phagocytosis by macrophages in the presence of cigarette smoke in relation to concomitant reduction in glyceraldehyde 3-phosphate dehydrogenase activity.

Immune enhancement of pulmonary bactericidal activity in murine virus pneumonia.

Bacterial multiplication in the lung associated with murine Sendai virus pneumonia is caused by virus-induced defects in pulmonary bactericidal mechanisms. The nature of this effect has been studied in animals immunized against the challenge bacteria. Mice were immunized against Proteus mirabilis by intraperitoneal inoculation and by aerosol inhalation. After the development of immunity, mice were infected aerogenically with 10(4) TCID(50) of Sendai virus. 7 days later, during the height of the bronchial inflammation and pulmonary consolidation, the mice were challenged with an aerosol of viable (35)S-labeled Proteus mirabilis or (32)P-labeled Staphylococcus aureus.Nonimmunized virus-infected animals showed marked impairment of pulmonary bactericidal activity with subsequent multiplication of the bacterial strain in the case of Proteus mirabilis. Immunized nonvirus-infected animals showed enhancement of pulmonary bactericidal activity for the homologous and heterologous strains in comparison with nonimmunized animals. Virus-infected animals immunized by aerosol showed enhanced bactericidal activity against the homologous but not the heterologous bacterial strain. Neither virus infection nor immunization had a significant effect on the transport of particles in the lung. The data demonstrated that the bacterial multiplication associated with the virus pneumonia was prevented by preceding immunization against the homologous challenge organism. The data suggest a mechanism for controlling bacterial multiplication associated with virus pneumonias.

Cost Effectiveness of a Preventive Program in Renal Disease

The practice of weighing the cost of preventive programs against the expected benefits is probably as old as prevention itself. The number of preventive programs has proliferated in the past few years and has forced a competition for limited funds. The need to set priorities for public health funding of such programs has, therefore, required a more detailed breakdown of both cost and benefit. For example, the benefits include the reductions in future mortality, hospitalization and sickness absenteeism resulting from the preventive program, each benefit being expressed in terms of dollars saved. The value of the reduction in the mortality of males is estimated from tables compiled by economists showing the average future productivity of males at various ages. Defining the value of a housewife is more difficult, however, and an arbitrary figure must be used. For this reason some program planners prefer to refer to the number of lives that will be saved and do not apply a monetary value. Because of the lack of agreement about the effectiveness of most preventive procedures in renal disease, and because many intangibles among the benefits defy precise evaluation, one may well ask what purpose is served in attempting to calculate the cost-benefit of any program. Apart from assisting the setting of priority in health planning, cost-benefit analysis is important in understanding the law of diminishing returns in expanding programs. Contrary to folklore that expanded programs automatically provide greater benefits, an analysis of the cost-benefit of several hypothetical programs of varying sizes will indicate the point at which further expansion leads to diminishing benefits.

Response to the Presentation on the Report of the President's Committee on Health Education

As it relates to the delivery of health care, and more broadly, to the quality of life, health education is an issue that is broad, complex, and, in its current form, fragmented. Although i t is desirable to achieve coordination and some degree of central direction in the development and operation of a program of such national importance, i t may be unwise to shift the responsibility for such a program entirely to a nationally oriented and centrally directed agency. As was recognized in the committee’s report, one of the most effective ways to improve behavior in regard to health matters through health education is to achieve participation in health planning and the education process at the community and individual level. It is in the spirit of such a participatory process !hat this Conference was organized and along such lines that it should proceed.