Inhibition of TLR9-NF-κB pathway‒mediated sterile inflammation improved PAB‒induced RV dysfunction in rats. This pathway plays a major role in the progression of pressure overload‒induced RV dysfunction, and is potentially a novel therapeutic target for the disorder.
We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset.
Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.
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