Delirium Prevention and Management in Frail Surgical Patients.

Delirium, an acute, fluctuating impairment in cognition and awareness, is one of the most common causes of postoperative brain dysfunction. It is associated with increased hospital length of stay, health care costs, and mortality. There is no FDA-approved treatment of delirium, and management relies on symptomatic control. Several preventative techniques have been proposed, including the choice of anesthetic agent, preoperative testing, and intraoperative monitoring. Frailty, a state of increased vulnerability to adverse events, is an independent and potentially modifiable risk factor for the development of delirium. Diligent preoperative screening techniques and implementation of prevention strategies could help improve outcomes in high-risk patients.

Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-ß (TGF-ß) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-ß. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-ß-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-ß and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-ß-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-ß bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-ß-induced myofibroblast differentiation. Gossypol inhibits TGF-ß-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-ß bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis.

Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-ß Induced Myofibroblast Differentiation via Prostaglandin E2.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor (TGF)-ß, fibroblasts co-cultured with epithelial cells expressed significantly less α-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-ß induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-ß promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-ß induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.