Respiratory dysfunction in old mice could be related to inflammation and lung fibrosis induced by hyperphosphatemia

Abstract

AbstractBackgroundWith age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age‐associated hyperphosphatemia in these changes.MethodsWe used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta‐glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET‐1 system by western blot or RT‐PCR.ResultsOld mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro‐inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP‐1 or FN promoters. BGP increased ECE‐1 expression by inducing NFkB binding to the ECE‐1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE‐1 was inhibited with phosphoramidon, BGP‐induced inflammation and fibrosis were significantly reduced, suggesting a role for ET‐1 in BGP‐mediated effects.ET‐1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low‐P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet.ConclusionThese results suggest that age‐related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET‐1 and NFkB activation.