On fire


Sepsis is an illness in which the body has a severe reaction to a bacterial infection. Bacterial toxins activate the immune system, causing widespread inflammation and increased blood calcium levels, oxidative stress, and inflammatory factors. This increased inflammation and immune activation can cause fatal organ damage, particularly in the lungs. Gandhirajan and colleagues identified a signaling pathway that mediates lung injury during sepsis. Treatment with a calcium channel blocker known as BTP2 halted sepsis-induced lung injury in mice. In the image above, Gandhirajan and colleagues used 2-photon imaging to examine the pulmonary vasculature in mice (image is false colored).  

Published January 25, 2013, by Jillian Hurst

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Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation
Rajesh Kumar Gandhirajan, … , Donald L. Gill, Muniswamy Madesh
Rajesh Kumar Gandhirajan, … , Donald L. Gill, Muniswamy Madesh
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):887-902. https://doi.org/10.1172/JCI65647.
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Research Article

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Abstract

During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1–dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPS-mediated Ca2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1–/– mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3–dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release–activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

Authors

Rajesh Kumar Gandhirajan, Shu Meng, Harish C. Chandramoorthy, Karthik Mallilankaraman, Salvatore Mancarella, Hui Gao, Roshanak Razmpour, Xiao-Feng Yang, Steven R. Houser, Ju Chen, Walter J. Koch, Hong Wang, Jonathan Soboloff, Donald L. Gill, Muniswamy Madesh

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