An Algorithm for Management After Transjugular Intrahepatic Portosystemic Shunt Placement According to Clinical Manifestations.

We propose an algorithm for management after transjugular intrahepatic portosystemic shunt (TIPS) placement according to clinical manifestations. For patients with an initial good clinical response, surveillance Doppler ultrasound is recommended to detect stenosis or occlusion. A TIPS revision can be performed using basic or advanced techniques to treat stenosis or occlusion. In patients with an initial poor clinical response, a TIPS venogram with pressure measurements should be performed to assess shunt patency. The creation of a parallel TIPS may also be required if the patient is symptomatic and the portal pressure remains high after TIPS revision. Additional procedures may also be necessary, such as peritoneovenous shunt (Denver shunt) placement for refractory ascites, tunneled pleural catheter for hepatic hydrothorax, and balloon-occluded retrograde transvenous obliteration procedure for gastric variceal bleeding. A TIPS reduction procedure can also be performed in patients with uncontrolled hepatic encephalopathy or hepatic failure.

Genetic deletion of the HIF-1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model.

Hypoxia-adenosinergic suppression and redirection of the immune response has been implicated in the regulation of antipathogen and antitumor immunity, with hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in antibacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis, we studied the function of I.1 isoform in T cells using mice with total I.1 isoform deficiency and mice with T-cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of proinflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest a previously unrecognized immunosuppressive role for the I.1 isoform in T cells during bacterial sepsis. We interpret these data as indicative that the activation-inducible isoform I.1 hinders the contribution of T cells to the antibacterial response by affecting M1/M2 macrophage polarization and microbicidal function.

A2B adenosine receptor expression by myeloid cells is proinflammatory in murine allergic-airway inflammation.

Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Because of its role in regulating myeloid cell-dependent inflammatory processes, we examined A(2B) R expression by myeloid cells in a cockroach allergen model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A(2B) R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and proinflammatory cytokine secretion after final allergen challenge in sensitized mice. A(2B) R deficiency resulted in a dramatic reduction on Th2-type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A(2B) R dependent. In contrast, there were no differences in the levels of the CXC chemokines keratinocyte-derived chemokine and MIP-2 in the myeloid cell A(2B) R-deficient mice, strengthening A(2B) R involvement in the development of Th2-type airways inflammation. Proinflammatory TNF-α, IFN-γ, and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A(2B) R deletion mouse lines. Our results demonstrate Th2-type predominance for A(2B) R expression by myeloid cells as a mechanism of development of asthma-like pulmonary inflammation.

Presence of preexisting antibodies mediates survival in sepsis.

Sepsis is one of the leading causes of death in hospitals worldwide. Even with optimal therapy, severe sepsis results in 50% mortality, indicating variability in the response of individuals towards treatment. We hypothesize that the presence of preexisting antibodies present in the blood before the onset of sepsis induced by cecal ligation and puncture (CLP) in mice accounts for the differences in their survival. A plasma-enhanced killing (PEK) assay was performed to calculate the PEK capacity of plasma, that is, the ability of plasma to augment polymorphonuclear neutrophil killing of bacteria. Plasma-enhanced killing was calculated as PEK = [1 / log (N)] × 100, where N = number of surviving bacteria; a higher PEK indicated better bacterial killing. A range of PEK in plasma collected from mice before CLP was observed, documenting individual differences in bacterial killing capacity. Mortality was predicted based on plasma IL-6 levels at 24 h after CLP. Mice predicted to die (Die-P) had a lower PEK (<14) and higher peritoneal bacterial counts at 24 h after sepsis compared with those predicted to live (Live-P) with a PEK of greater than 16. Mice with PEK of less than 14 were 3.1 times more likely to die compared with the group with PEK of greater than 16. To understand the mechanism of defense conferred by the preexisting antibodies, binding of IgM or IgG to enteric bacteria was documented by flow cytometry. To determine the relative contribution of IgM or IgG, the immunoglobulins were specifically immunodepleted from the naive plasma samples and the PEK of the depleted plasma measured. Compared with naive plasma, depletion of IgM had no effect on the PEK. However, depletion of IgG increased PEK, suggesting that an inhibitory IgG binds to antigenic sites on bacteria preventing optimal opsonization of the bacteria. These data demonstrate that, before CLP, circulating inhibitory IgG antibodies exist that prevent bacterial killing by polymorphonuclear neutrophils in a CLP model of sepsis.

A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice.

Antimicrobial treatment strategies must improve to reduce the high mortality rates in septic patients. In noninfectious models of acute inflammation, activation of A2B adenosine receptors (A2BR) in extracellular adenosine-rich microenvironments causes immunosuppression. We examined A2BR in antibacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Antagonism of A2BR significantly increased survival, enhanced bacterial phagocytosis, and decreased IL-6 and MIP-2 (a CXC chemokine) levels after CLP in outbred (ICR/CD-1) mice. During the CLP-induced septic response in A2BR knockout mice, hemodynamic parameters were improved compared with wild-type mice in addition to better survival and decreased plasma IL-6 levels. A2BR deficiency resulted in a dramatic 4-log reduction in peritoneal bacteria. The mechanism of these improvements was due to enhanced macrophage phagocytic activity without augmenting neutrophil phagocytosis of bacteria. Following ex vivo LPS stimulation, septic macrophages from A2BR knockout mice had increased IL-6 and TNF-α secretion compared with wild-type mice. A therapeutic intervention with A2BR blockade was studied by using a plasma biomarker to direct therapy to those mice predicted to die. Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival.