Endotoxemia is frequently used to delineate the pathophysiology of ALI. To characterize the temporal sequence of early events related to endotoxin-induced ALI, we infused 2 μg/kg of endotoxin (n = 5) or saline (n = 3) intravenously into anesthetized, mechanically ventilated, open chest sheep. We measured hemodynamics; collected blood samples every 30 min for 4 hr for arterial blood gases, cell counts, and cytokine measurements (ELISA); and took lung biopsies hourly for 4 hr for histology, EMSA detection of NF-kB, and real-time PCR analysis for cytokine gene transcription. All measurements in the control group were unchanged. Endotoxemia caused pulmonary hypertension (PVR peaked at 30 min, p < .01), hypoxemia (minimum PaO2 at 1 hr, p < .05), and persistent leukopenia and neutropenia (minimum WBC and PMN count at 90 min, p < .05). Interstitial thickness measured histologically increased, reaching a significant 78% increase at 4 hr (p < .05). Endotoxemia caused a 7.4-fold increase in lung tissue NF-kB (EMSA, p < .05). Lung mRNA and serum protein measurements defined a temporal cascade of inflammatory cytokines. Lung TNFa transcription peaked at 30 min (increased 63 6 15-fold, p < .05), followed by an IL-8 peak at 1 hr (186 6 122-fold, p < .05) followed by IL-6, which reached a maximal value at 4 hr (415 6 185-fold, p < .05). Serum levels of these cytokines showed the same temporal sequence. Serum IL-8 peaked at 2 hr (59-fold increase, p < .05), followed by an IL-6 peak at 3 hr (33-fold increase, p < .05). We conclude that endotoxemia causes an orchestrated cascade of inflammatory events in the lungs. Early pulmonary hypertension, leukopenia, and hypoxemia relate to production of TNFa while continued lung dysfunction and evolution of interstitial edema relate to sequential increases in IL-8 and IL-6.
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