Single-dose GSTP1 prevents infarction-induced heart failure.

BACKGROUND: Heart failure (HF) is a common and often fatal complication of myocardial infarction (MI). Glutathione S-transferase P1-1 (GSTP1) has antiapoptotic and antiinflammatory effects and is a specific serum marker in HF patients. However, its role in HF treatment is unknown. METHODS AND RESULTS: GSTP1 effect was examined in a rat MI-induced HF model. Magnetic resonance imaging was used to examine cardiac function. GSTP1 and tumor necrosis factor α receptor-associated factor 2 (TRAF2) mRNA and protein expression were elevated in failing myocardium, although GSTP-1 binding activity to TRAF2 was not changed versus control. HF was associated with higher active JNK1 and p38 protein expression but reduced GSTP-1 binding activity to JNK1 and p38. Recombinant GSTP1 inhibited JNK1 and p38 and enhanced its own binding activity to TRAF2 and JNK1 in vitro. In the HF model, single-dose GSTP1 treatment reduced infarct area, apoptosis, and the expression of JNK1, p38, nuclear factor κB, and proinflammatory cytokines and improved thinning ratio, cardiac index and output, stroke volume, ejection fraction, regional wall motion, and survival compared with control. CONCLUSIONS: GSTP1 application early after MI results in long-term beneficial structural and functional effects that prevent progression to HF. GSTP1 could be a novel adjunct myocardial salvage approach in patients after MI.

Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production.

Chromatin modifications, such as reversible histone acetylation, play a key role in the regulation of T cell development and function. However, the role of individual histone deacetylases (HDACs) in T cells is less well understood. In this article, we show by conditional gene targeting that T cell-specific loss of HDAC1 led to an increased inflammatory response in an in vivo allergic airway inflammation model. Mice with HDAC1-deficient T cells displayed an increase in all critical parameters in this Th2-type asthma model, such as eosinophil recruitment into the lung, mucus hypersecretion, parenchymal lung inflammation, and enhanced airway resistance. This correlated with enhanced Th2 cytokine production in HDAC1-deficient T cells isolated from diseased mice. In vitro-polarized HDAC1-deficient Th2 cells showed a similar enhancement of IL-4 expression, which was evident already at day 3 of Th2 differentiation cultures and restricted to T cell subsets that underwent several rounds of cell divisions. HDAC1 was recruited to the Il4 gene locus in ex vivo isolated nonstimulated CD4(+) T cells, indicating a direct control of the Il4 gene locus. Our data provide genetic evidence that HDAC1 is an essential HDAC that controls the magnitude of an inflammatory response by modulating cytokine expression in effector T cells.

Th2 related markers in milk allergic inflammatory mice model, versus OVA.

Experimental studies on allergic asthma are limited by the high cost of the administrated allergens. In this study we tested the allergic potency of low fat milk as a cheap substitute to the widely used standard allergen, ovalbumin (OVA). BALB/c female mice (4 weeks old) were sensitized intraperitoneally with low fat milk/or OVA followed by intranasal challenge with the two allergens on days 28 and 29. At day 31, serum, bronchoalveolar lavage fluid (BALF), and lungs were harvested. Mice of the low fat milk model showed infiltration of eosinophils, macrophages, lymphocytes, and neutrophils in BALF comparable to that of the OVA model. Both allergic protocols led to the production of similar numbers of Th2 cells and induced comparable expression of Th2 cytokine (IL-13) as evident by real time PCR for IL-13 and GATA3 (Th2 transcription factor) and confirmed by immunofluorescence for Th2 surface markers (T1/ST2). In addition, both mouse models had similar elevated levels of allergen specific antibody, IgG1 and IgE. Notably, HE, PAS, and LUNA stained lung sections from low fat milk treated mice had higher average pathological scores as compared to OVA treated mice. In conclusion, this study suggests that the low fat milk-induced inflammation showed hallmarks of allergic airway inflammatory model such as eosinophilic influx in BALF, increased numbers of Th2 cells, augmented expression of IL-13, elevated levels of circulatory IgG1 and IgE, signs of robust pulmonary inflammation, and most importantly it is a cheap and promising model for studying acute allergic airway inflammation and acute asthma.