Selective deficiency of HIF-1alpha in myeloid cells influences secondary intention wound healing in mouse skin.

Background: Hypoxia-inducible factor-1 (HIF-1) influences myeloid cell function. In this study we examined the role of myeloid cell HIF-1alpha on wound healing in vivo using a cell-specific knockout (KO) mouse model.

Materials And Methods: HIF-1alpha KO mice and wild-type (WT) controls received 8 mm full thickness dorsal dermal wounds.

Macrophage production of inflammatory mediators is potently inhibited by a butyric acid derivative demonstrated to inactivate antigen-stimulated T cells.

The butyric acid derivative, 2-(4-morpholynl) ethyl butyrate hydrochloride (MEB), has been reported to induce antigen-specific T cell unresponsiveness and to block T cell-mediated graft-versus-host disease. As a potential therapeutic agent, it was important to determine the effects of MEB on other cells that contribute to immunopathology. Accordingly, we tested the effects of MEB on macrophage functions.

Inhaled isobutyl nitrite inhibited macrophage inducible nitric oxide by blocking NFkappaB signaling and promoting degradation of inducible nitric oxide synthase-2.

We previously reported that inhaled isobutyl nitrite inhibited macrophage tumoricidal activity by inhibiting inducible nitric oxide (NO) production. In the present study, a much shorter inhalant exposure regimen (five daily exposures) inhibited inducible NO and the NO synthase (NOS2). One of the ways in which NO and NOS2 are regulated is by ubiquitin-dependent NOS2 degradation.

Cytotoxicity by nitrite inhalants is not related to peroxynitrite formation.

Nitrite inhalant abuse has been correlated with HIV and Kaposi's sarcoma. Mouse models of inhalant exposure show immunosuppression and loss of immune cells. In the present study, isobutyl nitrite caused a dose-dependent loss of viability of a macrophage cell line.