Division of Pulmonary, Allergy, and Critical Care Medicine, and.
Section of Mineral Metabolism, Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
Am J Respir Cell Mol Biol. 2024 Dec;71(6):659-676. doi: 10.1165/rcmb.2024-0008OC.
Chronic kidney disease (CKD) is associated with systemic phosphate elevations, called hyperphosphatemia. Translational studies have shown that hyperphosphatemia contributes to CKD-associated inflammation and injury in various tissues, including the kidney, heart, liver, and parathyroid gland. Mechanisms underlying pathologic actions of elevated phosphate on cells are not well understood but seem to involve uptake of phosphate through sodium phosphate cotransporters and phosphate-induced signaling via FGFR1 (fibroblast growth factor receptor 1). Clinical studies indicate patients with CKD are more likely to develop inflammatory and restrictive lung diseases, such as fibrotic interstitial lung diseases, and here we aimed to determine whether hyperphosphatemia can cause lung injury. We found that a mouse model of CKD and hyperphosphatemia, induced by an adenine-rich diet, develops lung fibrosis and inflammation. Elevation of systemic phosphate concentration by administration of a high-phosphate diet in a mouse model of primary lung inflammation and fibrosis, induced by bleomycin, exacerbated lung injury in the absence of kidney damage. Our studies identified increases of proinflammatory cytokines in human lung fibroblasts exposed to phosphate elevations. Phosphate activated ERK 1/2 (extracellular signal-related kinase 1/2) and PKB/AKT (protein kinase B) signaling, and pharmacological inhibition of ERK, AKT, FGFR1, or sodium phosphate cotransporters prevented phosphate-induced proinflammatory cytokine upregulation. In addition, inhibition of FGFR1 or sodium phosphate cotransporters decreased the phosphate-induced activation of ERK and AKT. Our study suggests that phosphate can directly target lung fibroblasts and induce an inflammatory response and that hyperphosphatemia in CKD and non-CKD models contributes to lung injury. Phosphate-lowering strategies might protect from CKD-associated lung injury.
慢性肾脏病（CKD）与全身磷酸盐升高有关，称为高磷血症。转化研究表明，高磷血症导致 CKD 相关的炎症和损伤在各种组织中，包括肾脏、心脏、肝脏和甲状旁腺。高磷酸盐对细胞的病理作用机制尚不清楚，但似乎涉及通过钠磷协同转运蛋白摄取磷酸盐，以及通过 FGFR1（成纤维细胞生长因子受体 1）进行磷酸盐诱导的信号传递。临床研究表明，CKD 患者更容易发生炎症性和限制性肺部疾病，如纤维化间质性肺疾病，我们旨在确定高磷血症是否会导致肺部损伤。我们发现，用富含腺嘌呤的饮食诱导的 CKD 和高磷血症小鼠模型会发展为肺纤维化和炎症。在博来霉素诱导的原发性肺炎症和纤维化小鼠模型中，通过给予高磷饮食来提高全身磷酸盐浓度，在没有肾脏损伤的情况下加剧了肺损伤。我们的研究在暴露于磷酸盐升高的人肺成纤维细胞中鉴定出促炎细胞因子的增加。磷酸盐激活 ERK1/2（细胞外信号相关激酶 1/2）和 PKB/AKT（蛋白激酶 B）信号通路，ERK、AKT、FGFR1 或钠磷协同转运蛋白的药理学抑制可防止磷酸盐诱导的促炎细胞因子上调。此外，抑制 FGFR1 或钠磷协同转运蛋白可降低磷酸盐诱导的 ERK 和 AKT 的激活。我们的研究表明，磷酸盐可以直接靶向肺成纤维细胞并诱导炎症反应，CKD 和非 CKD 模型中的高磷血症导致肺损伤。降低磷酸盐的策略可能有助于预防 CKD 相关的肺损伤。
