Effect of granulocyte colony-stimulating factor on acute lung injury in the rat.

The effect of G-CSF pretreatment on experimental acute lung injury was studied in Sprague-Dawley rats receiving one of the following treatments: (1) G-CSF 50 micrograms/kg subcutaneously twice daily beginning 2 d prior to being killed; (2) ANTU 50 mg/kg intraperitoneally; (3) ANTU+G-CSF 50, 25, or 12.5 micrograms/kg; (4) HCl 0.6 ml of a 0.1 N solution intratracheally; (5) HCl+G-CSF 50 or 25 micrograms/kg; (6) control solutions. Lung injury was quantified by measurement of lung wet/dry weights, by histopathologic scoring, and by measurement of fluid flux during ex vivo perfusion. G-CSF pretreatment elevated the baseline blood neutrophil counts as much as 6-fold compared with Control, and it increased the numbers of lung neutrophils and caused a mild histologic lung injury, but it did not significantly alter wet/dry weight ratios or fluid flux. ANTU alone and HCl alone caused a moderate histologic lung injury, increased wet/dry weight ratio, and resulted in a small increase in flux. The combination injuries, ANTU+G-CSF and HCl+G-CSF, caused a more severe lung injury manifested by increased wet/dry weight ratios and increase in flux when compared with ANTU alone and HCl alone, respectively. We conclude that pretreatment with G-CSF potentiates ANTU- and HCl-induced lung injury in non-neutropenic rats. The potential for G-CSF to aggravate acute lung injury in patients remains speculative.

Selection of patients for lung transplantation.

The number of lung and heart-lung transplantations is growing rapidly, and hundreds of combined heart-lung, single-lung, and double-lung transplantations have been performed to date, resulting in increased survival and improved quality of life for patients with end-stage pulmonary disorders. Improved surgical technique, immunosuppression, and optimal patient selection are largely responsible for this success. Although the indications for transplantation continue to expand, the number of potential recipients far exceeds the number of available donors, making the evaluation and selection process vital to the success of any transplantation program. A multidisciplinary approach is presented that can be expected to eliminate a large number of prospective candidates and thus enhance matching limited donor organs with transplantation candidates.

Effect of alkylating agents on the clearance of Staphylococcus aureus from murine lungs.

Alkylating agents have several effects on cellular host defense responses which could increase either the frequency or the severity of pulmonary infections. In addition, some of these agents directly injure lung parenchyma and could have effects on intrapulmonary killing processes independent of any effect on phagocyte number and function. We have used a murine model for staphylococcal clearance to evaluate the effect of cyclophosphamide and mechlorethamine on intrinsic lung defenses. Single doses of mechlorethamine (40 micrograms IV) or of cyclophosphamide (150 mg/kg IP) reduce peripheral blood neutrophil counts and spleen weights on day 3 after injection; with the exception of neutrophil counts in mechlorethamine-treated mice, these parameters returned to normal by days 10-12. Both drugs reduced the number of alveolar macrophages recoverable by bronchoalveolar lavage on days 10-12 but not day 3. Mechlorethamine delayed the clearance of Staphylococcus aureus 502A from the lung on both days 3 and 12, but cyclophosphamide did not alter clearance on either day 3 or 10. The defect in clearance in mechlorenthamine-treated mice resolved by 3 wk after drug administration. These results demonstrate that alkylating agents do not have uniform effects on antibacterial processes in the murine lung. Since the mechlorethamine effect on staphylococcal elimination appears independent of its effect on macrophage numbers, these results suggest that staphylococcal clearance also depends on nonphagocytic host defense factors.

Pulmonary tissue resistance to Candida albicans in normal and in immunosuppressed mice.

We characterized the clearance of Candida albicans from the lung using a murine model for pulmonary aspiration. Swiss Webster mice uniformly survived intratracheally administered boluses of C. albicans (1 to 30 X 10(5) colony-forming units of yeast) which killed the majority of mice (more than 85%) when injected intravenously. Clearance studies, using quantitative cultures of lung homogenates, demonstrated rapid elimination of C. albicans from the lung after a 6-h delay; the residual fractions of viable fungi were 8.3 and 0.7% of the initial inoculums at 24 and 48 h, respectively, after inoculation. The number of leukocytes in the bronchoalveolar spaces increased twofold to threefold after deposition, and this primarily reflected a neutrophil influx. Histologic studies supported the bronchoalveolar lavage results and revealed a diffuse interstitial neutrophilic infiltrate and clusters of inflammatory cells in air spaces at 6 and 24 h after Candida deposition. Examination of lavage pellets demonstrated that both neutrophils and macrophages ingested C. albicans in vivo. Immunosuppression (orally administered prednisolone for 2 wk) delayed the clearance of C. albicans from the lung. However, evaluation of neutrophil migration into bronchoalveolar spaces and of the in vivo ingestion capacity of both macrophages and neutrophils did not identify differences that could explain this delayed clearance in steroid-treated mice. The fungicidal activity of pulmonary leukocytes was measured with in vitro assays and was similar in phagocyte cultures from control and steroid-treated mice. In summary, intrinsic pulmonary defense factors and recruited neutrophils rapidly and completely clear C. albicans from the lung after bolus deposition.(ABSTRACT TRUNCATED AT 250 WORDS)

A morphological study of the role of phagocytes in the clearance of Staphylococcus aureus from the lung.

A nonlethal dose of Staphylococcus aureus was inoculated into the mainstem bronchus of mice in order to study the influx of polymorphonuclear leukocytes (PMN). The goal was to determine the routes of entry of PMN into the lung following bacterial challenge, the relative importance of PMN as compared to alveolar macrophages (AM) in the uptake of S aureus, and the role of lymphatics in clearance of intact microorganisms. Resident AM took up S aureus within minutes of inoculation, but PMN were subsequently recruited to the lung and were the predominant cell containing S aureus by 4 hours following inoculation. PMN were recruited from arteries, capillaries, and venules. Emigration of PMN into alveolar spaces occurred between type I epithelial cells as well as between type I and type II epithelial cells. Lymphatics played only a minor role in the clearance of S aureus.

Pulmonary clearance and phagocytic cell response to normal pharyngeal flora.

Because human lungs are repetitively inoculated with the normal bacterial flora of the pharynx, we determined the pulmonary clearance of representative species after aerosol inoculation of a murine model, and characterized the phagocytic cell response by bronchoalveolar lavage. Viable bacteria remaining in the lungs at 1, 2, and 4 h were: Streptococcus sanguis, 24%, 8%, and 1%; Streptococcus salivarius, 49%, 24%, and 5%; Neisseria catarrhalis, 69%, 49%, and 22%. Clearance of Streptococcus sanguis was associated with a twofold increase in alveolar macrophages (p less than 0.05); Streptococcus salivarius evoked a doubling of alveolar macrophages and a 20-fold rise in granulocytes (p less than 0.05); the response to Neisseria catarrhalis was a 400-fold increase in granulocytes (p less than 0.05). Thus, normal pharyngeal organisms are cleared rapidly from the lung by a dual phagocytic cell system. It is speculated that bacteria-phagocyte interaction allows the possibility of lung injury from proteolytic enzymes released from either set of phagocytes.