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

Abstract

With 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. We used C57BL6 mice to study an ageing model invivo 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. Old 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 invivo, 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. These 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.