Editors' ChoiceSepsis

Unmasking Lung Injury in Sepsis

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Science Translational Medicine  01 Aug 2012:
Vol. 4, Issue 145, pp. 145ec135
DOI: 10.1126/scitranslmed.3004662

In the 1998 blockbuster movie “The Mask of Zorro,” Antonio Banderas uses a mask to symbolize his change in behavior from a nobleman to an outlaw who defends the poor people of the land against tyrannical officials. In a new study, Schmidt and colleagues now propose that degradation of the extracellular surface layer (glycocalyx) of lung endothelium in mice with sepsis represents a “Zorro-like” switch from an anti-inflammatory to a proinflammatory state.

The glycocalyx of cells—composed of glycoproteins, proteoglycans, and glycosaminoglycans—is fragile and easily damaged by handling, which has made it difficult to analyze. Schmidt and colleagues tackle this problem using intravital microscopy to measure the thickness of the glycocalyx in the lung endothelium of mice before and during sepsis induced by bacterial lipopolysaccharide (LPS). They show that in the presence of circulating LPS, the thickness of the glycocalyx of endothelium-lining blood vessels in the lung is decreased compared with that of endothelium-lining blood vessels outside the lung. In isolated endothelial cells from the pulmonary microvasculature, LPS was found to induce cleavage and activation of heparanase, which was dependent on the proinflammatory cytokine tumor necrosis factor–α. Activated heparanase degrades heparan sulfate, a key component of the endothelial glycocalyx, resulting in the decreased thickness of the glycocalyx after LPS treatment. Treating mice with heparin, which blocks the degradation of heparin sulfate, prevented loss of the lung endothelial cell glycocalyx and reduced acute lung injury in mice exposed to LPS. The authors then showed, using anti-ICAM-1 microspheres, that loss of the glycocalyx exposes endothelial cell adhesion molecules that “trap” circulating neutrophils, thus exacerbating inflammation and lung injury. Last, Schmidt and co-workers attempted to connect their results in a mouse model to human patients. They found that serum from patients with respiratory failure due to sepsis had an increased ability to degrade heparan sulfate and that biopsies of injured human lung tissue had more heparanase activity than did healthy lung tissue.

Sepsis is a potentially life-threatening complication caused by bacterial infection, in which the body develops a severe systemic inflammatory response that affects many organs, including the lungs. By implicating degradation of the lung endothelial cell glycocalyx as a key event in the acute lung injury accompanying sepsis, Schmidt et al. reveal a new pathophysiological pathway that may yield new targets for therapeutic intervention.

E. P. Schmidt et al., The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat. Med., 22 July 2012 (10.1038/nm.2843). [PubMed]

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