Human pericardial proteoglycan 4 (lubricin): Implications for postcardiotomy intrathoracic adhesion formation

Abstract Objective Intra-pericardial fibrous adhesions increase the risk of sternal reentry. Lubricin/PRG4 is a mucin-like glycoprotein that lubricates tissue compartments and prevents inflammation. We characterized PRG4 expression in human pericardium and examined its effects in vitro on human cardiac myofibroblast fibrotic activity and in vivo as a measure of its therapeutic potential to prevent adhesions. Methods Full-length PRG4 expression was determined by Western blotting and AlphaLISA in human pericardial tissues obtained at cardiotomy. The in vitro effects of PRG4 were investigated on human cardiac myofibroblasts for cell adhesion, collagen gel contraction, and cell-mediated extracellular matrix remodeling. The influence of PRG4 on pericardial homeostasis was determined in a chronic porcine animal model. Results PRG4 is expressed in human pericardial fluid and co-localized with pericardial mesothelial cells. Recombinant human PRG4 prevented human cardiac myofibroblast attachment and reduced myofibroblast activity as assessed by collagen gel contraction assay (64.6%±8.1% vs 47.1%±6.8%, P=0.02). Using a microgel assay, human cardiac myofibroblast mediated collagen fiber remodeling was attenuated by PRG4 (1.17±0.03 vs 0.90±0.05, P=0.002). In vivo, removal of pericardial fluid alone induced severe intra-pericardial adhesion formation, tissue thickening, and inflammatory fluid collections. Restoration of intra-pericardial PRG4 was protective against fibrous adhesions and preserved the pericardial space. Conclusions For the first time, we show that PRG4 is expressed in human pericardial fluid and regulates local fibrotic myofibroblast activity. Loss of PRG4-enriched pericardial fluid after cardiotomy may induce adhesion formation. Therapeutic restoration of intra-pericardial PRG4 may prevent fibrous/inflammatory adhesions and reduce the risk of sternal re-entry.