Advertisement

This Month in AJP

    Open AccessPublished:May 28, 2012DOI:https://doi.org/10.1016/j.ajpath.2012.05.004

        HMGB1 Promotes NSAID-Induced Intestinal Damage

        Damaged cells release high-mobility group box 1 (HMGB1), activating inflammatory pathways via Toll-like receptors (TLRs) 2 and 4 and advanced glycation end products (RAGE). Nadatani et al (Am J Pathol 2012, 181:98–110) examined the role of HMGB1 in small intestinal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin. In wild-type mice, recombinant human HMGB1 aggravated indomethacin-induced small intestinal damage and enhanced mRNA expression of inflammatory cytokines and intracellular signaling molecules. Blocking HMGB1 with neutralizing antibodies prevented these effects. TLR2- and RAGE-knockout mice were highly sensitive to indomethacin, whereas TLR4-knockout mice exhibited less severe intestinal damage, reduced TNF-α mRNA expression, and no added effect from exogenous HMGB1. Thus, HMGB1 appears to promote NSAID-induced small intestinal damage via TLR4-dependent signaling.

        Linking Osteoporosis and Bone Marrow Failure after Pneumocystis Infection

        Aside from susceptibility to opportunistic infections such as Pneumocystis, unexplained complications in HIV+ and AIDS patients include osteoporosis and bone marrow failure, respectively. Wilkison et al (Am J Pathol 2012, 181:151–162) evaluated the potential connection between these bone pathologies following Pneumocystis lung infection in mice lacking both lymphocytes and type-I IFN receptor (IFrag−/−). Pneumocystis infection accelerated osteoclastogenesis as bone marrow failure progressed in these mice, consistent with induction of RANKL, TRAIL, and osteoprotegerin in the bone marrow of infected IFrag−/− mice. Biphosphonate treatment of IFrag−/− mice prevented bone loss and loss of hematopoietic precursor cells, which maintained activity in vitro; however, it did not prevent loss of mature neutrophils. Thus, deregulation of the RANKL/OPG/TRAIL axis—which is also deregulated in HIV+ individuals—connects the bone loss and bone marrow phenotypes in this model.

        VLPs Protect Against MRSA

        Priming the lung environment in anticipation of future lung infections could provide an important novel therapy for emerging infectious diseases. To test this, Rynda-Apple et al (Am J Pathol 2012, 181:196–210) administered virus-like particles (VLPs) to mice before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA). This protocol provided complete recovery from lung infection and near absolute clearance of bacteria within 12 hours, reduced host response-induced lung tissue damage, promoted recruitment and efficient bacterial clearance, and protected macrophages from MRSA-induced necrosis. Complete recovery occurred in VLP-dosed SCID mice but not in wild-type mice depleted of either Ly6G+ or CD11c+ cells. Early IL-13 production was also essential for protection. These results provide important insights into host anti-MRSA response mechanisms and suggest that VLPs could be a viable means of enhancing these mechanisms.

        Novel Axis Joins Stromal Cav-1 and mTOR Signaling

        To examine the effects of aging on mammary tumor growth, Mercier et al (Am J Pathol 2012, 181:278–293) used Cav-1 knockout (KO) mice as a model of accelerated host aging. Mammary tumor cells were orthotopically implanted into age-matched young female Cav-1+/+ and Cav-1−/− mice. Tumors grown in Cav-1 KO mammary fat pads were significantly larger and showed increased stromal content, including a proliferative stroma with hyperactivated mTOR signaling. Systemic rapamycin treatment of mammary tumors grown in a Cav-1 KO microenvironment significantly inhibited tumor growth, decreased stromal content, and reduced the levels of both vimentin (oxidative stress marker) and phospho-S6 (aging marker) in Cav-1 KO cancer-associated fibroblasts. These results using Cav-1–deficient mice as a pre-clinical model may have important translational significance for the diagnosis and the therapeutic stratification of breast cancer patients.

        Stem Cells Contribute to Vessel Graft Restenosis

        Neointimal lesions commonly occur in artificial vessel grafts used to treat occluded blood vessels. To clarify the cell types involved, Tsai et al (Am J Pathol 2012, 181:362–373) established a novel mouse model of restenosis by grafting a decellularized vessel to the carotid artery. Grafts developed neointimal lesions that contained endothelial (ECs) and smooth muscle cells (SMCs), monocytes, and stem/progenitor cells. In stem cell medium, explanted cultures of neointimal tissues displayed heterogeneous outgrowth, expressed c-kit, Sca-1, and CD34, and showed clonogenic and multilineage differentiation capacities. Sca-1+ cells could differentiate in vitro into ECs and SMCs in response to VEGF or PDGF-BB. In vivo local application of VEGF to decellularized vessels directed EC differentiation. Consequently, reduced SMC accumulation was observed, and the rate of neointimal formation was markedly reduced. Improved understanding of the cell types involved, together with the novel model system, may yield effective tools in the prevention or delay of restenosis.

        Linked Article

        • Caveolin-1 and Accelerated Host Aging in the Breast Tumor Microenvironment: Chemoprevention with Rapamycin, an mTOR Inhibitor and Anti-Aging Drug
          The American Journal of PathologyVol. 181Issue 1
          • Preview
            Increasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1+/+ versus Cav-1−/− age-matched young female mice). Mammary tumors grown in a Cav-1–deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging).
          • Full-Text
          • PDF
          Open Access
        • High Mobility Group Box 1 Promotes Small Intestinal Damage Induced by Nonsteroidal Anti-Inflammatory Drugs through Toll-Like Receptor 4
          The American Journal of PathologyVol. 181Issue 1
          • Preview
            Release of high mobility group box 1 (HMGB1) from damaged cells, which is involved in many types of tissue injuries, activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor 2 (TLR2), TLR4, and receptor for advanced glycation end-products (RAGE). Our objective was to determine the role of HMGB1 in nonsteroidal anti-inflammatory drug (NSAID)-induced damage of the small intestine. Oral indomethacin (10 mg/kg) induced damage to the small intestine and was associated with increases in intestinal HMGB1 expression and serum HMGB1 levels.
          • Full-Text
          • PDF
          Open Archive
        • Virus-Like Particle-Induced Protection Against MRSA Pneumonia Is Dependent on IL-13 and Enhancement of Phagocyte Function
          The American Journal of PathologyVol. 181Issue 1
          • Preview
            The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c+ cells, and iv) protects macrophages from MRSA-induced necrosis.
          • Full-Text
          • PDF
          Open Access
        • Type 1 Interferons Suppress Accelerated Osteoclastogenesis and Prevent Loss of Bone Mass During Systemic Inflammatory Responses to Pneumocystis Lung Infection
          The American Journal of PathologyVol. 181Issue 1
          • Preview
            HIV infection causes loss of CD4+ T cells and type 1 interferon (IFN)–producing and IFN-responsive dendritic cells, resulting in immunodeficiencies and susceptibility to opportunistic infections, such as Pneumocystis. Osteoporosis and bone marrow failure are additional unexplained complications in HIV-positive patients and patients with AIDS, respectively. We recently demonstrated that mice that lack lymphocytes and IFN a/b receptor (IFrag−/−) develop bone marrow failure after Pneumocystis lung infection, whereas lymphocyte-deficient, IFN α/β receptor–competent mice (RAG−/−) had normal hematopoiesis.
          • Full-Text
          • PDF
          Open Access
        • Contribution of Stem Cells to Neointimal Formation of Decellularized Vessel Grafts in a Novel Mouse Model
          The American Journal of PathologyVol. 181Issue 1
          • Preview
            Artificial vessel grafts are often used for the treatment of occluded blood vessels, but neointimal lesions commonly occur. To both elucidate and quantify which cell types contribute to the developing neointima, we established a novel mouse model of restenosis by grafting a decellularized vessel to the carotid artery. Typically, the graft developed neointimal lesions after 2 weeks, resulting in lumen closure within 4 weeks. Immunohistochemical staining revealed the presence of endothelial and smooth muscle cells, monocytes, and stem/progenitor cells at 2 weeks after implantation.
          • Full-Text
          • PDF
          Open Archive