Sphingosine-1-phosphate lyase is an endogenous suppressor of pulmonary fibrosis: role of S1P signalling and autophagy.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of fibroblasts and myofibroblasts and deposition of extracellular matrix proteins. Sphingosine-1-phosphate (S1P) signalling plays a critical role in pulmonary fibrosis. METHODS: S1P lyase (S1PL) expression in peripheral blood mononuclear cells (PBMCs) was correlated with pulmonary functions and overall survival; used a murine model to check the role of S1PL on the fibrogenesis and a cell culture system to study the effect of S1PL expression on transforming growth factor (TGF)-ß- and S1P-induced fibroblast differentiation. RESULTS: S1PL expression was upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. TGF-ß increased the expression of S1PL in human lung fibroblasts via activation and binding of Smad3 transcription factor to Sgpl1 promoter. Overexpression of S1PL attenuated TGF-ß-induced and S1P-induced differentiation of human lung fibroblasts through regulation of the expression of LC3 and beclin 1. Knockdown of S1PL (Sgpl1(+/-)) in mice augmented bleomycin-induced pulmonary fibrosis, and patients with IPF reduced Sgpl1 mRNA expression in PBMCs exhibited higher severity of fibrosis and lower survival rate. CONCLUSION: These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

Dementia with lewy bodies: therapeutic opportunities and pitfalls.

OBJECTIVE: To review diagnoses and challenges of treating patients with dementia with Lewy bodies (DLB), commonly considered the second most common form of dementia. DATA SOURCES: MEDLINE, Web of Science, and International Pharmaceutical Abstracts databases were searched in January 2006 for clinical studies, case series, case studies, letters, and review articles on the treatment of DLB. Search terms included: aripiprazole, cholinesterase inhibitors, clozapine, dementia with Lewy bodies, donepezil, galantamine, Lewy body dementia, neuroleptics, olanzapine, quetiapine, risperidone, rivastigmine, tacrine, ziprasidone. Applicable articles in the English language were reviewed. The bibliographies of these articles provided additional references. STUDY SELECTION: Articles describing studies, case series, and case studies are included in this review. DATA SYNTHESIS: DLB is commonly considered the second most common form of dementia, although some experts believe vascular dementia to be the second most common form. DLB is often under-diagnosed and misdiagnosed as Alzheimer's disease or Parkinson's related dementia. The core features of dementia with Lewy bodies are cognitive decline plus at least one of the following: fluctuations in cognition, visual hallucinations, and parkinsonism. Other supportive features include: neuroleptic sensitivity, repeated falls, syncope, transient loss of consciousness, REM sleep disturbances, depression, delusions, and nonvisual hallucinations. CONCLUSION: Increased prudence with the use of neuroleptic agents is essential in DLBs because the use of these agents is associated with physical and cognitive decline and increased mortality. While neuroleptic sensitivity has been reported with the use of both typical and atypical antipsychotic medications, these medications are often necessary for the treatment of psychotic symptoms. Decreases in neuroleptic sensitivity can often be achieved by dose reductions, although neuroleptic discontinuation is sometimes necessary. Cholinesterase inhibitors may be especially useful in the treatment of DLB. Cholinergic deficits are associated with visual hallucinations, and cholinesterase inhibitors often result in resolution of hallucinations, improved cognition, and decreased behavioral disturbances.