The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Abstract

Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

Interaction of environmental Burkholderia cenocepacia strains with cystic fibrosis and non-cystic fibrosis bronchial epithelial cells in vitro

“…This is in agreement with the finding that defects in CFTR trafficking, such as those documented in DF508CFTR-expressing cells, cause alterations of the cytoskeleton (Favia et al, 2010), plasma membrane, or membrane-interacting proteins (Guerra et al, 2005) and tight junctions (LeSimple et al, 2010;Nilsson et al, 2010). To date, trafficking of DF508CFTR has been related to some CF defects such as alteration of ceramide metabolism (Becker et al, 2010) and NAPDH oxidase activation (Zhang et al, 2008). Herein we suggest that the observed alteration of tight junctions in CF epithelial cells may be responsible for the differential susceptibility to infection by B. cenocepacia strains.…”

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

“…In the inflammatory disease cystic fibrosis, ceramides induce the upregulation of proinflammatory mediators by a yet unknown mechanism (11). In the current study, we demonstrate that C 16:0 -Cer is involved in the induction of EAE through activation of NO/TNF-a synthesis.…”

Ceramide synthesis regulates T cell activity and GVHD development

“…In the thymus, while T cell compartments were similar in WT and CerS4 KO mice, a significant increase in percentages of CD4 Ceramides are critical for inflammatory responses (16). In the inflammatory disease cystic fibrosis, ceramides induce the upregulation of proinflammatory mediators (11). In addition, C16-ceramide (C16-cer) generated by CerS6 is involved in the induction of EAE through activation of NO/TNF-α synthesis (12).…”

“…In the aforementioned study, lack of host acid SMase reduced the acute inflammatory phase of GVHD, attenuating the cytokine storm (10). In the inflammatory disease cystic fibrosis, ceramides induce the upregulation of proinflammatory mediators, albeit via an unknown mechanism (11). Importantly, CerS6-generated ceramides were shown to specifically contribute to the inflammatory process in the initial phase of experimental autoimmune encephalomyelitis (EAE) (12).…”