Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn’s disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18. In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3−/− and wild-type (WT) mice were assessed in the DSS- and TNBS-models of experimental colitis. Nlrp3−/− mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β reduced anti-inflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3−/− mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3−/− mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions and a unique intestinal microbiota. Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.

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ARDS is associated with poor clinical outcomes, with a pooled mortality rate of approximately 40% despite best standards of care. Current therapeutic strategies are based on improving oxygenation and pulmonary compliance while minimizing ventilator-induced lung injury. It has been demonstrated that relative hypoxemia can be well tolerated, and improvements in oxygenation do not necessarily translate into survival benefit. Cardiac failure, in particular right ventricular dysfunction (RVD), is commonly encountered in moderate to severe ARDS and is reported to be one of the major determinants of mortality. The prevalence rate of echocardiographically evident RVD in ARDS varies across studies, ranging from 22% to 50%. Although there is no definitive causal relationship between RVD and mortality, severe RVD is associated with increased mortality. Factors that can adversely affect RV function include hypoxic pulmonary vasoconstriction, hypercapnia, and invasive ventilation with high driving pressure. It might be expected that early diagnosis of RVD would be of benefit; however, echocardiographic markers (qualitative and quantitative) used to prospectively evaluate the right ventricle in ARDS have not been tested in adequately powered studies. In this review, we examine the prognostic implications and pathophysiology of RVD in ARDS and discuss available diagnostic modalities and treatment options. We aim to identify gaps in knowledge and directions for future research that could potentially improve clinical outcomes in this patient population.

In this report, we show for the first time that ceramide-1-phosphate (C1P) stimulates the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway, which is a major mechanism whereby growth factors promote cell survival. Also, C1P induced IjB phosphorylation, and enhanced the DNA binding activity of the transcription factor NF-jB. Apoptotic macrophages showed a marked reduction of Bcl-X L levels, and this was prevented by C1P. These findings suggest that C1P blocks apoptosis, at least in part, by stimulating the PI3-K/ PKB/ NF-jB pathway and maintaining the production of antiapoptotic Bcl-X L . Based on these and our previous observations, we propose a working model for C1P in which inhibition of acid sphingomyelinase and the subsequent decrease in ceramide levels would allow cell signaling through stimulation of the PI3-K/PKB pathway to promote cell survival.

Numerous therapies used for inflammatory bowel disease (IBD) target the transcription factor NF-kappaB, which is involved in the production of cytokines and chemokines integral for inflammation. Here we show that curcumin, a component of the spice turmeric, is able to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-induced murine model of colitis. When given before the induction of colitis it reduced macroscopic damage scores and NF-kappaB activation. This was accompanied by a reduction in myeloperoxidase activity, and using semiquantitative RT-PCR, an attenuation of the DNB-induced message for IL-1beta was detected. Western blotting analysis revealed that there was a reproducible DNB-induced activation of p38 MAPK detected in intestinal lysates by using a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, we show that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. We conclude that the widely used food additive curcumin is able to attenuate experimental colitis through a mechanism correlated with the inhibition of the activation of NF-kappaB and effects a reduction in the activity of p38 MAPK. We propose that this agent may have therapeutic implications for human IBD.