Cytochrome P-450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess potent anti-inflammatory effects in vitro. However, the effect of increased CYP-mediated EET biosynthesis and decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on vascular inflammation in vivo has not been rigorously investigated. Consequently, we characterized acute vascular inflammatory responses to endotoxin in transgenic ... More
G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms.
AuthorsDonini M, Fontana S, Savoldi G, Vermi W, Tassone L, Gentili F, Zenaro E, Ferrari D, Notarangelo LD, Porta F, Facchetti F, Notarangelo LD, Dusi S, Badolato R
JournalBlood
PubMed ID17311988
'The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous ... More
Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia.
AuthorsLi Y, Jia Y, Pichavant M, Loison F, Sarraj B, Kasorn A, You J, Robson BE, Umetsu DT, Mizgerd JP, Ye K, Luo HR,
JournalBlood
PubMed ID19286998
'Neutropenia and related infections are the most important dose-limiting toxicities in anticancer chemotherapy and radiotherapy. In this study, we explored a new strategy for augmenting host defense in neutropenia-related pneumonia. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3''-phosphatase that hydrolyzes PtdIns(3,4,5)P(3). In myeloid-specific PTEN knockout ... More
Inflammation-induced, 3'UTR-dependent translational inhibition of Hsp70 mRNA impairs intestinal homeostasis.
AuthorsHu S, Zhu X, Triggs JR, Tao Y, Wang Y, Lichtenstein L, Bissonnette M, Musch MW, Chang EB,
JournalAm J Physiol Gastrointest Liver Physiol
PubMed ID19299581
'Although the inducible heat shock protein 70 (Hsp70) is essential for maintaining intestinal homeostasis in colitis, it is translationally downregulated in inflamed colonic mucosa, paradoxically rendering the gut more susceptible to injury. We examined the basis for this process by analyzing the role of untranslated regions (UTR) of Hsp70 mRNA ... More
Functional consequence of positive selection revealed through rational mutagenesis of human myeloperoxidase.
'Myeloperoxidase (MPO) is a member of the mammalian heme peroxidase (MHP) multigene family. Whereas all MHPs oxidize specific halides to generate the corresponding hypohalous acid, MPO is unique in its capacity to oxidize chloride at physiologic pH to produce hypochlorous acid (HOCl), a potent microbicide that contributes to neutrophil-mediated host ... More
E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection.
AuthorsAronoff DM, Lewis C, Serezani CH, Eaton KA, Goel D, Phipps JC, Peters-Golden M, Mancuso P,
JournalJ Immunol
PubMed ID19635910
Prostaglandins (PGs) are potent lipid mediators that are produced during infections and whose synthesis and signaling networks present potential pharmacologic targets for immunomodulation. PGE(2) acts through the ligation of four distinct G protein-coupled receptors, E-prostanoid (EP) 1-4. Previous in vitro and in vivo studies demonstrated that the activation of the ... More
Dectin-1 promotes fungicidal activity of human neutrophils.
AuthorsKennedy AD, Willment JA, Dorward DW, Williams DL, Brown GD, DeLeo FR,
JournalEur J Immunol
PubMed ID17230442
Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied on monocytes and ... More
Increased iron content and RNA oxidative damage in skeletal muscle with aging and disuse atrophy.
AuthorsHofer T, Marzetti E, Xu J, Seo AY, Gulec S, Knutson MD, Leeuwenburgh C, Dupont-Versteegden EE,
JournalExp Gerontol
PubMed ID18395385
Muscle atrophy with aging or disuse is associated with deregulated iron homeostasis and increased oxidative stress likely inflicting damage to nucleic acids. Therefore, we investigated RNA and DNA oxidation, and iron homeostasis in gastrocnemius muscles. Disuse atrophy was induced in 6- and 32-month old male Fischer 344/Brown Norway rats by ... More