A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury in mice.

Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivated in vivo is not fully understood. Here, we present evidence that a highly conserved host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine. AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell death in vitro and acute lung injury in mice.

A host lipase prevents lipopolysaccharide-induced foam cell formation.

Although microbe-associated molecular pattern (MAMP) molecules can promote cholesterol accumulation in macrophages, the existence of a host-derived MAMP inactivation mechanism that prevents foam cell formation has not been described. Here, we tested the ability of acyloxyacyl hydrolase (AOAH), the host lipase that inactivates gram-negative bacterial lipopolysaccharides (LPSs), to prevent foam cell formation in mice. Following exposure to small intraperitoneal dose(s) of LPSs, macrophages produced more low-density lipoprotein receptor and less apolipoprotein E and accumulated more cholesterol than did macrophages.

Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness.

Although organ hypofunction and immunosuppression are life-threatening features of severe sepsis, the hypofunctioning organs and immune cells usually regain normal functionality if patients survive. Because tissue interstitial fluid can become acidic during the septic response, we tested the hypothesis that low extracellular pH (pHe) can induce reversible metabolic and functional changes in peritoneal macrophages from C57BL/6J mice. When compared with macrophages cultured at normal pHe, macrophages living in an acidic medium used less glucose and exogenous fatty acid to produce ATP.

Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery.

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis.

A Cross-Country Network Analysis of Adolescent Resilience.

Purpose: In situations of adversity, young people draw on individual, relational, and contextual (community and cultural) resources to foster their resilience. Recent literature defines resilience as a capacity that is underpinned by a network of interrelated resources. Although empirical studies show evidence of the value of a network approach, little is known regarding how different country contexts influence which resources are most critical within a resource network and how resources interact for adolescent resilience.

Positive youth development practices and better outcomes for high risk youth.

This paper reports on the findings from a New Zealand longitudinal study of outcomes for a group of high risk, service-using youth (13-21 years, n=495). Consistent use of positive youth development practices (PYD) (rather than the total number of services used) predicted better outcomes. Patterns of risk and resilience endured over time.

Endotoxemia-menace, marker, or mistake?

Endotoxemia is in its scientific ascendancy. Never has blood-borne, Gram-negative bacterial endotoxin (LPS) been invoked in the pathogenesis of so many diseases-not only as a trigger for septic shock, once its most cited role, but also as a contributor to atherosclerosis, obesity, chronic fatigue, metabolic syndrome, and many other conditions. Finding elevated plasma endotoxin levels has been essential supporting evidence for each of these links, yet the assays used to detect and quantitate endotoxin have important limitations.

LPS stimulates IgM production in vivo without help from non-B cells.

Gram-negative bacterial LPS induce murine B-cell activation and innate (polyclonal) Ab production. Mouse B cells express the LPS signaling receptor (TLR4), yet how LPS activates B-cell responses in vivo is not known. Can LPS directly stimulate B cells to induce innate Ab production? Is activation of non-B cells also required? To address these questions, we transfused LPS-responsive (Tlr4(+/+)) or non-responsive (Tlr4(-/-)) B cells into LPS-responsive or non-responsive mice.

Implementing a new governance model.

Purpose - The purpose of this paper is to discuss the lessons learnt from the process of implementing a new model of governance within Living Well, a New Zealand statutory mental health agency. Design/methodology/approach - It presents the findings from an organisational case study that involved qualitative interviews, meeting observations and document analysis. Archetype theory provided the analytical framework for the research enabling an analysis of both the formal structures and informal value systems that influenced the implementation of the governance model.

Patterns of individual coping, engagement with social supports and use of formal services among a five-country sample of resilient youth.

Background: Although resilience among victims of child abuse is commonly understood as a process of interaction between individuals and their environments, there have been very few studies of how children's individual coping strategies, social supports and formal services combine to promote well-being.

Method: For this study, we conducted a multi-phase analysis of a qualitative dataset of 608 interviews with young people from five countries using grounded theory strategies to build a substantive theory of young people's service and support use patterns. We started with an analysis of ten interviews (two from each country) and then compared these findings to patterns found in each country's full dataset.

The role of positive youth development practices in building resilience and enhancing wellbeing for at-risk youth.

Services that utilise positive youth development practices (PYD) are thought to improve the quality of the service experience leading to better outcomes for at-risk youth. This article reports on a study of 605 adolescents (aged 12-17 years) who were concurrent clients of two or more service systems (child welfare, juvenile justice, additional education, mental health). It was hypothesised that services adopting PYD approaches would be related to increases in youth resilience and better wellbeing outcomes.

The role of government policy in service development in a New Zealand statutory mental health service: implications for policy planning and development.

Objective: To explore the relationship between government policy and service development in a New Zealand statutory mental health provider, Living Well.

Method: An organisational case study utilising multiple research techniques including qualitative interviews, analysis of business and strategic documents and observation of meetings.

Results: Staff understood and acknowledged the importance of government policy, but there were challenges in its implementation.

A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity.

The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases.

Prolonged triglyceride storage in macrophages: pHo trumps pO2 and TLR4.

Lipid-laden macrophages contribute to pathologies as diverse as atherosclerosis and tuberculosis. Three common stimuli are known to promote macrophage lipid storage: low tissue oxygen tension (pO2), low extracellular pH (pHo), and exposure to agonists such as bacterial LPS. Noting that cells responding to low pO2 or agonistic bacterial molecules often decrease pHo by secreting lactic and other carboxylic acids, we studied how pHo influences the stimulation of triacylglycerol (TAG) storage by low pO2 and LPS.

Toll-like receptor agonists promote prolonged triglyceride storage in macrophages.

Macrophages in infected tissues may sense microbial molecules that significantly alter their metabolism. In a seeming paradox, these critical host defense cells often respond by increasing glucose catabolism while simultaneously storing fatty acids (FA) as triglycerides (TAG) in lipid droplets. We used a load-chase strategy to study the mechanisms that promote long term retention of TAG in murine and human macrophages.

Multiple service use: the impact of consistency in service quality for vulnerable youth.

Little is known about the way in which variations in service quality influence outcomes when youth are clients of more than one service system. This article reports on a study of 1,210 adolescents (aged 13-17 years), half were concurrent clients of two or more services and half were not involved in two or more services. Youth completed a self-report questionnaire administered by a trained interviewer.

Persistently active microbial molecules prolong innate immune tolerance in vivo.

Measures that bolster the resolution phase of infectious diseases may offer new opportunities for improving outcome. Here we show that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function.

Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes.

Much evidence indicates that bacterial LPS (endotoxin) is removed from the bloodstream mainly by the liver, yet the hepatic uptake mechanisms remain uncertain and controversial. In plasma, LPS can be either 'free' (as aggregates, bacterial membrane fragments or loosely bound to albumin, CD14, or other proteins) or 'bound' (complexed with lipoproteins). Whereas most free LPS is taken up by Kupffer cells (KCs), lipoprotein-bound LPS has seemed to be cleared principally by hepatocytes.

The transport and inactivation kinetics of bacterial lipopolysaccharide influence its immunological potency in vivo.

The extraordinary potency and pathological relevance of gram-negative bacterial LPSs have made them very popular experimental agonists, yet little is known about what happens to these stimulatory molecules within animal tissues. We tracked fluorescent and radiolabeled LPS from a s.c.

Novel therapies for septic shock over the past 4 decades.

Infections that result in shock and organ failure are a major public health problem worldwide. Severe sepsis and septic shock affect patients of all ages and often complicate chronic diseases. They are the major causes of death in critical care units and contribute substantially to hospital inpatient costs.

Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin.

Unlabelled: Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS-induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS.

Overproduction of acyloxyacyl hydrolase by macrophages and dendritic cells prevents prolonged reactions to bacterial lipopolysaccharide in vivo.

Although recognition of lipopolysaccharide (LPS) by the myeloid differentiation factor 2-Toll-like receptor 4 complex is important for triggering protective inflammatory responses in animals, terminating many of these responses requires LPS inactivation by a host lipase, acyloxyacyl hydrolase (AOAH). To test whether endogenously produced recombinant AOAH can modulate responses to LPS and gram-negative bacteria, we engineered transgenic mice that overexpress AOAH in dendritic cells and macrophages, cell types that normally produce it. Transgenic mice deacylated LPS more rapidly than did wild-type controls.

Chapter 2: Kill the bacteria...and also their messengers?

We consider here a previously neglected aspect of recovery from infectious diseases: how animals dispose of the dead microbes in their tissues. For one of the most important disease-causing microorganisms, Gram-negative bacteria, there is now evidence that the host catabolism of a key microbial molecule is essential for full recovery. As might be expected, it is the same bacterial molecule that animals sense to detect the presence of Gram-negative bacteria in their tissues, the cell wall lipopolysaccharide (LPS).