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Chong-Jeh Lo, MD; Iris Garcia; H. Gill Cryer, MD, PhD; Ronald V. Maier, MD

Arch Surg. 1996;131(1):44-50.

Abstract
Background
Alterations in macrophage (M) function are responsible, in part, for adult respiratory distress syndrome and multiple organ failure developing in patients with sepsis. Elucidation and control of these M 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 M production of tumor necrosis factor (TNF) and procoagulant (PC) activity.

Design
Rabbit alveolar M 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 M. Elevating intracellular calcium ([Ca²⁺]i), using the calcium ionophore, A23187, or thapsigargin alone, did not induce M 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 M.

(Arch Surg. 1996;131:44-50)

Author Affiliations
From the Departments of Surgery, University of California, Los Angeles (Drs Lo and Cryer), and University of Washington, Seattle (Ms Garcia and Dr Maier).

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