Pulmonary Antibacterial Mechanisms Research Articles

Pulmonary Oxygen Toxicity

<h2>Summary</h2> Oxygen is essential to human life but the products of its metabolism are potentially harmful to lung tissue. Manifestation of these harmful effects follows a sequence of pathological changes involving cellular proliferation, exudation and interstitial fibrosis. Changes in the alveolar capillary membrane give rise to altered metabolic pathways in the lung which can have a subsequent effect on aspects of care directly related to physiotherapy; for example, a progressive dose-related deterioration in pulmonary antibacterial mechanisms has been demonstrated, suggesting a progressive deterioration in host resistance to inhaled bacteria with prolonged exposure to high oxygen tension. This supports the clinical impression that prolonged oxygen therapy increases susceptibility of the lung to infection. Patients primarily at risk from pulmonary oxygen toxicity are those requiring long-term mechanical ventilation as a result of multisystem failure — with or without prior pulmonary insult — who demonstrate the need for high inspired oxygen concentrations, hence the lungs are in an hyperoxic environment. An accurate and cost-effective method of detecting early onset of metabolic pathway variation is as yet unavailable. Such a method would reflect damage to the pulmonary endothelium prior to clinical evidence of damage, and facilitate diagnosis before the development of irreversible lung damage. Research is currently directed towards monitoring the disruption of uptake of vaso-active amines to produce a quantitative assessment as an indicator of pulmonary microvascular injury. Careful and precise monitoring of ‘therapeutic levels' of oxygen is needed in conjunction with thorough understanding of the potential problems. This should enable a balance between adequate oxygenation to relieve tissue hypoxia, while minimising the risks of developing toxic damage.

The Effect of Common Pharmacologic Agents on Pulmonary Antibacterial Defenses: Implications for the Geriatric Patient

Clinical and laboratory observations have raised the possibility that common pharmacologic agents disrupt lung host defense and predispose to bacterial infection of the lower respiratory tract. Epidemiologic data suggest that the potential for an impairment in pulmonary antibacterial mechanisms is greatest among individuals of advanced age. However, lung antimicrobial systems are extremely complex, and patients with pulmonary infections characteristically have a variety of predisposing conditions. Thus, it remains very difficult to assess the relative impact of drug-related derangements on lung antimicrobial systems. Indeed, it is likely that multiple intrinsic and extrinsic factors contribute to the evolution of most bacterial pneumonias. Thus, while medications may not represent major risk factors, they may act in an additive or synergistic manner with other predisposing conditions, such as age-associated changes in immunologic activity and underlying disease, to enhance susceptibility to infectious illnesses of the lung. Clearly, substantial clinical and laboratory study will be required in order to define the role that common pharmacologic agents play in predisposing to bacterial infection of the lower respiratory tract.

Cimetidine does not impair lung host defense in experimental pneumococcal pneumonia.

Normal CD-1 mice were administered cimetidine (400 mg/kg/24 h) or control solution by subcutaneous injection and inoculated intratracheally with type S Streptococcus pneumoniae in order to evaluate the effect of the histamine H2-receptor antagonist on pulmonary antibacterial mechanisms. Therapy with cimetidine did not influence overall survival rates. After challenge with 1 X 10(6) colony-forming units (cfu), the eradication of viable pneumococci from the lungs (pulmonary clearance), the generation of a local inflammatory response, and the prevalence of bacteremia were similar in both study groups. Cimetidine also failed to influence pulmonary antimicrobial systems after challenge with lower bacterial inocula (5 X 10(4) and 5 X 10(3) cfu). Further, treatment with cimetidine had no effect on the in vivo phagocytic or bactericidal activity of resident murine alveolar macrophages. Thus, in this animal model, cimetidine does not disrupt host defenses of the lower respiratory tract.

Ascorbate modulates antibacterial mechanisms in experimental pneumococcal pneumonia.

To evaluate the influence of vitamin C on pulmonary antibacterial mechanisms, normal CD-1 mice were administered sodium ascorbate (200 mg/kg/24 h) and challenged intratracheally with type 3 Streptococcus pneumoniae. Survival rates were similar in ascorbate-treated and control animals. When infected with a high inoculum (1 X 10(6) cfu), animals given vitamin C demonstrated a significant enhancement in their capacity to clear viable pneumococci from the lungs at 24 h after challenge; the augmented pulmonary clearance was associated with an increased influx of granulocytes at 6 and 24 h. After infection with a lower inoculum (1 X 10(5) cfu), animals treated with the vitamin exhibited a significant advantage in pulmonary clearance and granulocyte recruitment but at 6 h only. After a very low inoculum challenge (1 X 10(4) cfu), the clearance of viable pneumococci was retarded in ascorbate-treated mice. In vitro, the pneumococcidal capacity of resident alveolar macrophages from animals given vitamin C was significantly reduced, but the ability of these cells to generate leukocyte chemoattractant activity after stimulation with the calcium ionophore A23187 remained unaltered. We conclude that in the mouse, large doses of vitamin C alter pulmonary defense mechanisms against S. pneumoniae; however, these changes do not appear to convey a substantial advantage to the host.

Digoxin disrupts the inflammatory response in experimental pneumococcal pneumonia.

Digoxin was administered to normal CD-1 mice (4 micrograms/kg per 24 hr), and the mice were inoculated intratracheally with Streptococcus pneumoniae in order to assess the effects of the cardiac glycoside on pulmonary antibacterial mechanisms. Digoxin-treated animals experienced a worse survival rate than did controls (19 of 50 versus 33 of 50; P less than .01). When challenged with a high inoculum (1 X 10(6) cfu), animals given the glycoside demonstrated a significant impairment in their capacity to clear viable pneumococci from the lungs; the depression in pulmonary clearance was associated with a marked attenuation in the ability of digoxin-treated mice to recruit granulocytes and macrophages into the bronchoalveolar spaces. Following low inoculum challenge (1 X 10(5) cfu), animals treated with the cardiac glycoside exhibited an inefficient pulmonary clearance and a blunted macrophage influx. At clinically relevant concentrations, digoxin demonstrated no effect on the in vitro pneumococcidal activity of resident murine alveolar macrophages. We conclude that digoxin can disrupt host defense against pneumococcus by impeding the normal inflammatory response to organisms deposited into the lower respiratory tract.

Interaction of influenza virus with swine alveolar macrophages: Influence of anti-virus antibodies and cytochalasin B

SummaryInteractions between swine influenza virus and swine alveolar macrophages were studied in vitro. Cell lysis occurred 24 h post-infection and was shown by a decreased neutral red uptake. UV inactivation of the influenza virus, or the addition of anti-influenza antibodies suppressed the virus-induced macrophage lysis. Inversely, pretreatment of swine alveolar macrophages by a phagocytosis inhibitor, namely cytochalasin B, increased the cell susceptibility to virus-induced lysis.The present in vitro studies support the hypothesis that defects in pulmonary antibacterial mechanisms associated with influenza infections are partly due to a direct toxic effect of the virus on alveolar macrophages. Furthermore, the studies show that virus-induced macrophage lysis is influenced by specific humoral immune responses and by modifications in microfilament cell functions.

Effect of influenza infection on the phagocytic and bactericidal activities of pulmonary macrophages.

The effect of mouse-adapted influenza A/PR/8/34 virus on pulmonary macrophage function was evaluated by using an in vitro system which allowed direct virus interaction with macrophages and then separate analysis of the steps required for bacterial clearance by macrophages. Infection of macrophages with this virus resulted in the appearance of a hemagglutinating activity on the macrophage surface; expression of this activity was inhibited by amantadine, 2-deoxyglucose, and cycloheximide and by pretreatment of the virus inoculum with ultraviolet light and specific antiserum. Since there was no release of extracellular virus, this growth cycle appeared to be incomplete (abortive). After influenza infection, net ingestion of viable Staphylococcus aureus by macrophage monolayers was unaltered and there was no change in the fraction of the monolayer which ingested cocci over a wide range of bacterial inputs. Influenza-infected macrophages also inactivated intracellular S. aureus at a rate indistinguishable from controls. Therefore, these in vitro studies do not support the hypothesis that the defect in pulmonary antibacterial mechanisms associated with influenza infections results from a direct effect of virus infection on either the phagocytic or bactericidal activity of resident pulmonary macrophages.

Alteration of the pathogenicity of Pasteurella pneumotropica for the murine lung caused by changes in pulmonary antibacterial activity.

Pasteurella pneumotropica is a potential pulmonary pathogen in mice. In healthy animals, this organism was killed rapidly by the normal function of the intrapulmonary phagocytic defense mechanisms. Impairment of this bactericidal activity by the acute renal failure of nephrectomy resulted in multiplication of the Pasteurella in the lung, both when the animals were nephrectomized first and then infected, and when the animals were infected first and nephrectomized several hours after the infection. The study demonstrates that the pathogenicity of the Pasteurella organisms is governed by the functional state of these pulmonary antibacterial mechanisms.