Persistent inflammation and fibrosis of the lung are long-term complications of sepsis in baboons (P4015)

Abstract

Abstract Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrotic responses. We have developed a baboon model of E. coli sepsis-induced ARDS and characterized the long-term (6-24 months) effects of sepsis on the lung. By immunocytochemistry, we detected focal accumulation of neutrophils, M2 macrophages, IL17 and TGF-β positive cells, which indicates persistent inflammation in the lung, months after clinical recovery from the acute sepsis episode. Microscopical and biochemical quantification demonstrated an almost doubling of collagen content amount in the lungs of animals that survived sepsis as compared to age-matched nonexposed controls. Electron microscopy showed myofibroblast accumulation within the alveolar wall. Co-staining for fibroblast and cell proliferation markers demonstrated active cell proliferation in fibroblastic foci. Immunostaining with antibodies to procollagens showed active collagen synthesis within the fibroblastic foci and interalveolar septa. These fibroblasts were also stained with phospho Smad-2 and CTGF antibodies, suggesting that TGF-β signaling was one of the main mediators of fibrosis. In conclusion, we show that E. coli sepsis-induced ARDS triggers chronic inflammation, fibroblast proliferation and collagen deposition in the primate. These long-lasting fibrotic responses perpetuate the lung injury and may contribute to post ARDS morbidity and mortality observed in humans.