Abstract
Hypertonic saline (HTS) has been used intravenously to reduce organ dysfunction following injury and as an inhaled therapy for cystic fibrosis lung disease. The role and mechanism of HTS inhibition was explored in the TNFα and IL-1β stimulation of pulmonary epithelial cells. Hyperosmolar (HOsm) media (400 mOsm) inhibited the production of select cytokines stimulated by TNFα and IL-1β at the level of mRNA translation, synthesis and release. In TNFα stimulated A549 cells, HOsm media inhibited I-κBα phosphorylation, NF-κB translocation into the nucleus and NF-κB nuclear binding. In IL-1β stimulated cells HOsm inhibited I-κBα phosphorylation without affecting NF-κB translocation or nuclear binding. Incubation in HOsm conditions inhibited both TNFα and IL-1β stimulated nuclear localization of interferon response factor 1 (IRF-1). Additional transcription factors such as AP-1, Erk-1/2, JNK and STAT-1 were unaffected by HOsm. HTS and sorbitol supplemented media produced comparable outcomes in all experiments, indicating that the effects of HTS were mediated by osmolarity, not by sodium. While not affecting MAPK modules discernibly in A549 cells, both HOsm conditions inhibit IRF-1 against TNFα or IL-1β, but inhibit p65 NF-kB translocation only against TNFα but not IL-1β. Thus, anti-inflammatory mechanisms of HTS/HOsm appear to disrupt cytokine signals at distinct intracellular steps.
Highlights
Hypertonic saline (HTS) has been used to treat post-traumatic acute lung injury (ALI) [1, 2, 3] and the acute respiratory distress syndrome (ARDS) [4, 5]
To investigate potential anti-inflammatory effects of HOsm on A549 cells, the stimulated production of inflammatory cytokines and chemokines were measured in response to Tumor necrosis factor-a (TNFa) and interleukin 1b (IL-1b)
This panel covers the production of various CC and CXC chemokines, growth factors and interleukins that could signal other cells in the pulmonary alveoli such as macrophages, neutrophils and T-cells, disposing toward TH1, 2 or 17 phenotypes
Summary
Hypertonic saline (HTS) has been used to treat post-traumatic acute lung injury (ALI) [1, 2, 3] and the acute respiratory distress syndrome (ARDS) [4, 5]. Tumor necrosis factor-a (TNFa) and interleukin 1b (IL-1b) are pro-inflammatory cytokines [9, 10] whose signaling pathways are expressed ubiquitously in human cells and induce expression of multiple proinflammatory cytokines and chemokines. Both TNFa and IL-1b play important roles in pulmonary inflammation and have been implicated in the development of ALI following hemorrhagic shock. Inhibition of these cytokines has been previously shown to diminish lung inflammation [11, 12, 13, 14, 15, 16]
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