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Calcium and Calmodulin Regulate Lipopolysaccharide-Induced Alveolar Macrophage Production of Tumor Necrosis Factor and Procoagulant Activity

Chong-Jeh Lo, MD; Iris Garcia; H. Gill Cryer, MD, PhD; Ronald V. Maier, MD
Arch Surg. 1996;131(1):44-50. doi:10.1001/archsurg.1996.01430130046008.
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Background:  Alterations in macrophage (Mϕ) function are responsible, in part, for adult respiratory distress syndrome and multiple organ failure developing in patients with sepsis. Elucidation and control of these Mϕ mechanisms during sepsis are crucial to our understanding of this disease and, ultimately, to improving survival of these patients.

Objective:  To investigate the involvement of calcium flux in endotoxin-induced alveolar Mϕ production of tumor necrosis factor (TNF) and procoagulant (PC) activity.

Design:  Rabbit alveolar Mϕ obtained by bronchoalveolar lavage were exposed to endotoxin in the form of lipopolysaccharide (LPS) extracted from Escherichia coli 0111:B4 in the presence of different specific calcium agonists and antagonists. The TNF expression was measured in the supernatant by L929 bioassays. The PC activity was determined in cell lysates by a one-step coagulation assay.

Results:  Macrophages activated by LPS produce enormous levels of TNF and PC. Either W7 (20 μmol/L), a calmodulin antagonist, or TMB-8 (50 μmol/L), which prevents calcium release from the endoplasmic reticulum, inhibited production of both TNF and PC activity. Verapamil (50 μmol/L) alone or combined with TMB-8 significantly inhibited both TNF and PC production by LPS-stimulated Mϕ. Elevating intracellular calcium ([Ca2+]i), using the calcium ionophore, A23187, or thapsigargin alone, did not induce Mϕ production of TNF but significantly augmented LPS-stimulated TNF production.

Conclusion:  Our results indicate that increased intracellular calcium causing signal transduction activation through the calmodulin pathway is a necessary, but insufficient, component of the LPS signaling in Mϕ.(Arch Surg. 1996;131:44-50)


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