Many microbial pathogens subvert proteoglycans for their adhesion to host tissues, invasion of host cells, infection of neighbouring cells, dissemination into the systemic circulation, and evasion of host defence mechanisms. Where studied, specific virulence factors mediate these proteoglycan–pathogen interactions, which are thus thought to affect the onset, progression and outcome of infection. Proteoglycans are composites of glycosaminoglycan (GAG) chains attached covalently to specific core proteins. Proteoglycans are expressed ubiquitously on the cell surface, in intracellular compartments, and in the extracellular matrix. GAGs mediate the majority of ligand-binding activities of proteoglycans, and many microbial pathogens elaborate cell-surface and secreted factors that interact with GAGs. Some pathogens also modulate the expression and function of proteoglycans through known virulence factors. Several GAG-binding pathogens can no longer attach to and invade host cells whose GAG expression has been reduced by mutagenesis or enzymatic treatment. Furthermore, GAG antagonists have been shown to inhibit microbial attachment and host cell entry in vitro and reduce virulence in vivo. Together, these observations underscore the biological significance of proteoglycan–pathogen interactions in infectious diseases.

In pneumonia caused by the bacterium Staphylococcus aureus, the intense inflammatory response that is triggered by this infection can lead to the development of lung injury. Little is known, however, about the impact of specific virulence factors on this inflammatory disorder, which causes both significant mortality and morbidity. In this study, we examined the role of ␤-toxin, a neutral sphingomyelinase, in S. aureus-induced lung injury. Our results showed that the central features of lung injury-specifically, increased neutrophilic inflammation, vascular leakage of serum proteins into the lung tissue, and exudation of proteins into the airway-are significantly attenuated in mice infected intranasally with S. aureus deficient in ␤-toxin compared with mice infected with S. aureus expressing ␤-toxin. In addition, intranasal administration of ␤-toxin evoked the characteristic features of lung injury in wild-type mice whereas neutropenic mice were protected from such injury. However, mutant ␤-toxin mice deficient in sphingomyelinase activity failed to trigger features of lung injury. Ablation of sphingomyelinase activity also interfered with the ability of ␤-toxin to stimulate ectodomain shedding of syndecan-1, a major heparan sulfate proteoglycan found in epithelial cells. Moreover, syndecan-1-null mice were significantly protected from ␤-toxin-induced lung injury relative to wild-type mice. These data indicate that S. aureus ␤-toxin is a critical virulence factor that induces neutrophil-mediated lung injury through both its sphingomyelinase activity and syndecan

These data suggest that alpha-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia.

The extracellular domain of several membrane-anchored proteins is released from the cell surface as soluble proteins through a regulated proteolytic mechanism called ectodomain shedding. Cells use ectodomain shedding to actively regulate the expression and function of surface molecules, and modulate a wide variety of cellular and physiological processes. Ectodomain shedding rapidly converts membrane-associated proteins into soluble effectors and, at the same time, rapidly reduces the level of cell surface expression. For some proteins, ectodomain shedding is also a prerequisite for intramembrane proteolysis, which liberates the cytoplasmic domain of the affected molecule and associated signaling factors to regulate transcription. Ectodomain shedding is a process that is highly regulated by specific agonists, antagonists, and intracellular signaling pathways. Moreover, only about 2% of cell surface proteins are released from the surface by ectodomain shedding, indicating that cells selectively shed their protein ectodomains. This review will describe the molecular and cellular mechanisms of ectodomain shedding, and discuss its major functions in lung development and disease.

Left Panel: Lung tissue from a mouse 28 days post‐treatment with bleomycin. The tissue section, which was stained with Gomori's Trichrome stain shows increased collagen (blue) in the lung parenchyma. Right Panel: In situ binding assay showing the binding of rhCXCL8 to alveolar macrophages, alveolar septa, and the cell surface of airway epithelial cells. In this confocal image, rhCXCL8 is stained red, nuclei are stained with ToPro‐3 (Blue), and tissue autofluorescence (green) provides structural details. See Hayashida et al., on page 925, in this issue.

BACKGROUND AND OBJECTIVES:There has been a rapid increase in the rate of pediatric opioidrelated hospitalizations. It is unknown how this increase has impacted the use of pediatric critical care. Our objective in this study was to assess the trends in pediatric hospitalization for opioid ingestions in a cohort of US children's hospitals and, specifically, to evaluate the impact on pediatric critical care resource use.

Heparan sulfate proteoglycans bind to and regulate many inflammatory mediators in vitro, suggesting that they serve an important role in influencing inflammatory responses in vivo. Here we evaluated the role of syndecan-1, a major heparan sulfate proteoglycan, in modulating inflammatory responses in Gram-positive toxic shock, a systemic disease that is a significant cause of morbidity and mortality. Syndecan-1-null and wild-type mice were injected intraperitoneally with staphylococcal enterotoxin B, a pyrogenic superantigen, and their inflammatory responses were assessed. Syndecan-1-null mice showed significantly increased liver injury, vascular permeability, and death in response to staphylococcal enterotoxin B challenge compared with wild-type mice. Although serum levels of systemic IL-2 and IFN␥ were similar between the two backgrounds, those of TNF␣ and IL-6 were significantly increased in syndecan-1-null mice undergoing Gram-positive toxic shock. Furthermore, syndecan-1-null mice challenged with staphylococcal enterotoxin B showed enhanced T cell accumulation in tissues, whereas immunodepletion of T cells protected syndecan-1-null mice from the magnified systemic cytokine storm, inflammatory tissue injury, and death. Importantly, syndecan-1 shedding was induced in wild-type mice injected with staphylococcal enterotoxin B, and the administration of heparan sulfate, but not syndecan-1 core protein, rescued syndecan-1-null mice from lethal toxic shock by suppressing the production of TNF␣ and IL-6, and attenuating inflammatory tissue injury. Altogether, these data suggest that syndecan-1 shedding is a key endogenous mechanism that protects the host from Gram-positive toxic shock by inhibiting the dysregulation and amplification of the inflammatory response.

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