Hypoxia, a microenvironmental factor present in diseased tissues, has been recognized as a specific metabolic stimulus or a signal of cellular response. Experimental hypoxia has been reported to induce adaptation in macrophages such as differential migration, elevation of proinflammatory cytokines and glycolytic enzyme activities, and decreased phagocytosis of inert particles. In this study we demonstrate that although exposure to hypoxia (5% O2, 5% CO2, and balanced N2) did not change macrophage viability, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cleavage and proliferation, it significantly reduced expression of the 70-kD heat shock protein (HSP70), which was restored to prehypoxia levels after reoxygenation. The influence of low oxygen tension on macrophage functional activity was also studied, i.e. the ability of these cells to maintain or resist infection by a microorganism. We demonstrate that macrophages from two different sources (a murine cell line and primary cells) exposed to hypoxia were efficiently infected with Leishmania amazonensis, but after 24 h showed a reduction in the percentage of infected cells and of the number of intracellular parasites per macrophage, indicating that hypoxia induced macrophages to kill the intracellular parasites. These results support the notion that hypoxia, a microenvironmental factor, can modulate macrophage protein expression and functional activity.
[Show abstract][Hide abstract] ABSTRACT: The present study was undertaken to examine the involvement of nitric oxide (NO) and excitotoxicity in the development of hypoxia-induced retinopathy in adult rats.
Retinas of adult rats were examined at 3 hours to 14 days after hypoxia. The mRNA and protein expression of endothelial, neuronal, and inducible nitric oxide synthase (eNOS, nNOS, and iNOS, respectively), hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), N-methyl-D-aspartate receptor subunit 1 (NMDAR1), and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate (AMPA GluR2 and GluR3) receptors in the retina was determined by real-time RT-PCR, Western blot analysis, and immunohistochemistry. The response of retinal microglial cells to hypoxia was also studied by immunohistochemistry.
Hemorrhages were observed in the retina after hypoxia. Upregulated mRNA and protein expression of HIF-1alpha, NMDAR1, GluR2, GluR3, VEGF, eNOS, nNOS, and iNOS in the retina was observed in response to hypoxia. Complement type 3 (CR3) receptors and major histocompatibility complex (MHC) class I and II antigen expression on the microglial cells was increased after exposure to hypoxia.
The findings of this study indicate that NO and excitotoxicity may produce damage to retina in response to hypoxia. Increased expressions of eNOS and VEGF in response to hypoxia are indicative of vasodilatation and increased permeability of retinal blood vessels. Increased phagocytosis by retinal microglial cells evidenced by increased expression of CR3 receptors may occur for the removal of hemorrhagic debris. Upregulation of MHC antigens indicates the readiness of these cells to participate in an immune response.
[Show abstract][Hide abstract] ABSTRACT: Regions of low oxygen tension are common features of inflamed and infected tissues and provide physiologic selective pressure for the expansion of cells with enhanced hypoxia tolerance. The aim of this study was to investigate whether macrophages resistant to death induced by hypoxia were accompanied by functional alterations. A mouse macrophage cell line (J774 cells) was used to obtain subpopulations of death-resistant macrophages induced by long-term exposure to severe hypoxia (<1% O(2)). The results indicated that exposing J774 macrophages to periods of severe hypoxia results in the selection of cells with phenotypes associated with the modulation of heat-shock protein 70 kDa (HSP70) expression, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production and reduced susceptibility to parasite Leishmania infection. Thus, we suggest that hypoxia-selected macrophages may influence the outcome of inflammation and infection.
Experimental Biology and Medicine 02/2007; 232(1):88-95. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence indicates that hypoxia-inducible factor 1alpha (HIF-1alpha) can be upregulated in different cell types by nonhypoxic stimuli such as growth factors, cytokines, nitric oxide, lipopolysaccharides and a range of infectious microorganisms. In this study, the ability of the following mononuclear phagocytes to express HIF-1alpha is reported: mouse macrophages (mMPhi), human macrophages (hMPhi) and human dendritic cells (DC), parasitized in vitro with Leishmania amazonensis; as assessed by immunofluorescence microscopy. A logical explanation for HIF-1alpha expression might be that the mononuclear phagocytes became hypoxic after L. amazonensis infection. Using the hypoxia marker pimonidazole, observation revealed that L. amazonensis-infected cells were not hypoxic. In addition, experiments using a HIF-1alpha inhibitor, CdCl(2), to treat L. amazonensis-infected macrophage cultures showed reduced parasite survival. These studies indicated that HIF-1alpha could play a role in adaptative and immune responses of mononuclear phagocytes presenting infection by the parasite L. amazonensis.
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