DDR is stably associated with the cellular senescence condition. The biology of SAA has been investigated extensively. SAA is a key mediator in innate immune responses, stimulation of cytokines, and matrix metalloproteinases. Biological activities include regulation of cholesterol metabolism, insulin resistance and glycemic control. During acute phase, SAA displaces 80% of ApoAI from HDL. Elevated levels of SAA are down-regulated by therapy with PPARγ agonist agents, whereas glucocorticoid treatment did not Pazopanib downregulate extrahepatic expression of SAA. In chronic inflammatory diseases, such as rheumatoid arthritis, metabolic syndrome or atherosclerosis, prolonged elevation of SAA may contribute to tissue damage and degradation. Elevated SAA contributes to AA amyloidosis if abnormal cleavage and deposition occurs in genetically predisposed individuals. SAA was shown to regulate expression of TGF-β, the master regulator of connective tissue remodeling and fibrogenesis. In mice, SAA adenoviral transfer leads to increased plasma TGF-β, and increased biglycan expression. Interestingly, it has been reported that the SAA receptor FPRL-1/FPR2 was involved in TGF-β, as well as in biglycan expression. These studies implicate SAA in extracellular matrix remodeling. The role of inflammation in SSc, and biomarkers for identifying inflammation, have received scant attention to date. Previous studies showed that erythrocyte sedimentation rate is elevated in SSc and predicts mortality. ESR is one of the parameters comprising the modified Medsger SSc Disease Severity Scale. Levels of CRP are also elevated in SSc, correlate with disease activity and pulmonary function, and predict pulmonary decline and survival. In contrast to CRP and ESR, little is known to date about SAA in SSc or its role in disease pathogenesis. A small pilot study over three decades ago showed elevated SAA levels in 24% of SSc patients; marked elevations predicted poor survival. In the present study, we sought to determine circulating levels of SAA in SSc, and to correlate these levels with clinical features of the disease. Our findings indicate that SAA levels are elevated in a subset of SSc patients, and correlate with pulmonary involvement and patient-reported outcomes, in particular symptoms related to respiratory dysfunction. In vitro, recombinant SAA induced enhanced IL-6 and IL-8 production in fibroblasts explanted from normal human lungs. These findings provide evidence for the occurrence of a systemic inflammatory process in SSc, and suggest a potential for SAA as a biomarker in evaluating patients with SSc. We show here that circulating levels of the inflammatory marker SAA are elevated in patients with SSc. Elevated SAA levels are associated with signs and symptoms of pulmonary involvement, as well as health-related quality of life measures. In particular, levels of SAA were found to correlate with measures of pulmonary function and radiologic evidence of SSc-associated interstitial lung disease. Furthermore, SAA levels were significantly correlated with PA pressure, in a manner analogous to recent findings in patients with idiopathic pulmonary arterial hypertension. Exposure of healthy lung fibroblasts in culture to SAA resulted in stimulation of the expression of IL-6 and IL-8, two cytokines previously implicated in the pathogenesis of SSc. The levels of SAA were only modestly correlated with those of the inflammatory markers CRP and ESR. While levels of CRP and ESR were elevated in 29 and 37% of SSc patients, respectively, the correlation with SAA was less than 0.5, revealing unexpected differences in these three inflammatory parameters in SSc.