Treatment of antineutrophil cytoplasmic antibody-associated vasculitis.

PURPOSE OF REVIEW: The primary idiopathic small-vessel vasculitis syndromes include granulomatosis with polyangiitis, Churg-Strauss syndrome, and microscopic polyangiitis. These disorders are commonly referred to as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides and prominently affect the pulmonary vasculature. Although significant progress has been made in the management of these disorders, they continue to carry substantial morbidity and mortality as a result of both the underlying vasculitis as well as complications of its immunosuppressive therapy. This review will focus on the recent advances in the management and longitudinal monitoring of ANCA-associated vasculitis. RECENT FINDINGS: Cyclophosphamide and glucocorticoids are standard therapy, but carry measureable risk of treatment-related toxicity. The search for alternative therapies that are less toxic but similarly efficacious is continuing. Recent investigations suggest rituximab may be a well tolerated alternative to cyclophosphamide for the induction of remission, treatment of disease relapse, and as maintenance therapy. SUMMARY: The ANCA-associated vasculitides are a group of disorders that commonly affect the pulmonary vasculature and represent a diagnostic and therapeutic challenge to the pulmonary clinician. Recent findings have expanded our ability to diagnose and treat these disorders with a focus on limiting treatment-related toxicity while inducing and maintaining remission.

Assessments of the chemistry and vasodilatory activity of nitrite with hemoglobin under physiologically relevant conditions.

Hypoxic vasodilation involves detection of the oxygen content of blood by a sensor, which rapidly transduces this signal into vasodilatory bioactivity. Current perspectives on the molecular mechanism of this function hold that hemoglobin (Hb) operates as both oxygen sensor and a condition-responsive NO reactor that regulates the dispensing of bioactivity through release of the NO group from the beta-cys93 S-nitroso derivative of Hb, SNO-Hb. A common path to the formation of SNO-Hb involves oxidative transfer of the NO-group from heme to thiol. We have previously reported that the reaction of nitrite with deoxy-Hb, which furnishes heme-Fe(II)NO, represents one attractive route for the formation of SNO-Hb. Recent literature, however, posits that the nitrite-reductase reaction of Hb might produce physiological vasodilatory effects through NO that evades trapping on heme-Fe(II) and may be stored before release as Fe(III)NO. In this article, we briefly review current perspectives in NO biology on the nitrite-reductase reaction of Hb. We report in vitro spectroscopic (UV/Vis, EPR) studies that are difficult to reconcile with suggestions that this reaction either generates a heme-Fe(III)NO reservoir or significantly liberates NO. We further show in bioassay experiments that combinations of nitrite and deoxy-Hb--under conditions that suppress SNO-Hb formation--exhibit no direct vasodilatory activity. These results help underscore the differences between physiological, RBC-regulated, hypoxic vasodilation versus pharmacological effects of exogenous nitrite.

Routes to S-nitroso-hemoglobin formation with heme redox and preferential reactivity in the beta subunits.

Previous studies of the interactions of NO with human hemoglobin have implied the predominance of reaction channels that alternatively eliminate NO by converting it to nitrate, or tightly complex it on the alpha subunit ferrous hemes. Both channels could effectively quench NO bioactivity. More recent work has raised the idea that NO groups can efficiently transfer from the hemes to cysteine thiols within the beta subunit (cysbeta-93) to form bioactive nitrosothiols. The regulation of NO function, through its chemical position in the hemoglobin, is supported by response to oxygen and to redox agents that modulate the molecular and electronic structure of the protein. In this article, we focus on reactions in which Fe(III) hemes could provide the oxidative requirements of this NO-group transfer chemistry. We report a detailed investigation of the reductive nitrosylation of human met-Hb, in which we demonstrate the production of S-nitroso (SNO)-Hb through a heme-Fe(III)NO intermediate. The production of SNO-Hb is strongly favored (over nitrite) when NO is gradually introduced in limited total quantities; in this situation, moreover, heme nitrosylation occurs primarily within the beta subunits of the hemoglobin tetramer. SNO-Hb can similarly be produced when Fe(II)NO hemes are subjected to mild oxidation. The reaction of deoxygenated hemoglobin with limited quantities of nitrite leads to the production of beta subunit Fe(II)NO hemes, with SNO-Hb produced on subsequent oxygenation. The common theme of these reactions is the effective coupling of heme-iron and NO redox chemistries. Collectively, they establish a connectivity between hemes and thiols in Hb, through which NO is readily dislodged from storage on the heme to form bioactive SNO-Hb.