Liposome-encapsulated hemoglobin does not exacerbate endotoxin-induced lung injury.

OBJECTIVE: To test the hypothesis that liposome encapsulated hemoglobin (LEH), an experimental oxygen-carrying fluid, exacerbates endotoxin-induced lung injury in the rat. DESIGN: Prospective, randomized animal study. SETTING: University animal laboratory. METHODS: Anesthetized Sprague-Dawley rats (n = 8-13) were infused with LEH (10% of estimated total blood volume) or vehicle (0.9% NaCl). Thirty minutes later, Escherichia coli endotoxin (3.6 mg/kg, i.v.) or vehicle (0.9% NaCl) was administered, and skeletal muscle oxygen tension as well as lung injury were assessed at 2, 4, and 8 hrs. Oxygen tension was measured using a miniaturized thin film oxygen sensor placed in the rectus abdominis muscle, and lung injury was evaluated by determining lung weights, lung myeloperoxidase activity, lung tissue tumor necrosis factor-alpha level, and protein concentration in bronchoalveolar lavage fluid. RESULTS: The intravenous bolus injection of E. coli endotoxin elevated lung water content (33% +/- 5%; p < .01 vs. sham controls), myeloperoxidase activity (56% +/- 6%; p < .01), and tumor necrosis factor-alpha production (1320 +/- 154 pg/g lung tissue; p < .05 vs. undetected levels in sham controls), as well as induced protein accumulation in bronchoalveolar lavage fluid (258% +/- 38%; p < .01) and skeletal muscle hypoxia (52 +/- 8 mm Hg; p < .05). Pretreatment with LEH, which when infused alone did not induce lung injury, had no effect on these responses. CONCLUSION: In this specific model of endotoxin-induced lung injury, LEH does not exacerbate microvascular leakage and leukosequestration, the hallmarks of adult respiratory distress syndrome.

Locally produced tumor necrosis factor-alpha mediates interleukin-2-induced lung injury.

Interleukin (IL)-2-induced microvascular lung injury is an experimental paradigm commonly used to investigate the pathogenesis of the adult respiratory distress syndrome. Since tumor necrosis factor-alpha (TNF-alpha) is known to induce such an injury in vivo and since TNF-alpha is involved in other models of lung injury, we postulated that it might also mediate pulmonary toxicity after IL-2 administration. The present study tested this hypothesis by evaluating the effect of TNF-alpha inhibition on IL-2-induced lung injury in the rat. Recombinant human IL-2 (10(6) U IV per rat, n = 6) elevated lung water, myeloperoxidase activity, and protein accumulation in bronchoalveolar lavage fluid and induced tissue hypoxia. Also, IL-2 enhanced lung tissue TNF-alpha mRNA and peptide (1543 +/- 496 pg/g lung wet weight) localized to alveolar macrophages by in situ hybridization. In marked contrast, IL-2 failed to affect serum TNF-alpha, which remained at undetectable levels. Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia. Furthermore, TNF-alpha inhibition prevented the upregulation of lung tissue IL-1 beta, IL-6, cytokine-induced neutrophil chemoattractant, and E-selectin (ELAM-1) but not intercellular adhesion molecule-1 mRNAs in response to IL-2. These data imply that locally produced TNF-alpha mediates IL-2-induced lung inflammation and tissue injury and point to the potential utilization of TNF-alpha inhibitors in treating the pulmonary toxicity of IL-2 immunotherapy.

Aspiration-induced lung injury: role of complement.

OBJECTIVES: To examine the role of complement in the development of acid aspiration-induced lung injury in the rat. It was postulated that inhibition or depletion of complement attenuates aspiration-induced lung injury. DESIGN: Controlled animal trial. SETTING: Animal Laboratory, Jefferson Medical College, Philadelphia, PA. SUBJECTS: Anesthetized rats. INTERVENTIONS: Aspiration was induced by the intratracheal administration of 0.2 mL of 0.1 N hydrochloric acid (n = 7) and lung injury was evaluated by determining water content, myeloperoxidase activity, protein concentration, and leukocyte count in bronchoalveolar lavage fluid. Muscle PO2 was directly measured using a thin-film chamber oxygen sensor and serum tumor necrosis factor-alpha was assayed by enzyme-linked immunosorbent assay. The effect of complement inhibition by recombinant human soluble complement receptor type 1 (n = 8) or complement depletion by cobra venom factor (n = 7) on lung injury was evaluated. MEASUREMENTS AND MAIN RESULTS: Acid aspiration induced pulmonary leukosequestration, edema, and a microvascular permeability defect, along with tissue hypoxia. Pretreatment with soluble complement receptor type 1 (complement inhibition) or cobra venom factor (complement depletion) significantly reduced lung edema (-61 +/- 7%; p < .05), eliminated protein accumulation in bronchoalveolar lavage fluid (p < .01), and improved (p < .05) tissue oxygenation. In contrast, there was no effect of soluble complement receptor type 1 or of cobra venom factor on leukosequestration. CONCLUSIONS: Acid aspiration induces lung injury through a complement-dependent mechanism that leads to microvascular permeability defects. Therefore, the possibility that complement inhibitors may have a salutary effect in humans with aspiration-induced lung injury should be investigated.