Secreted phospholipase A2 XIIA triggers a mitochondrial damage-induced senescence in chronic obstructive pulmonary disease fibroblasts.

RATIONALE: Lung fibroblast senescence is involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlining this phenomenon are still poorly understood. Secreted phospholipases (sPLA2, a subclass of phospholipases) are secreted by senescent cells and can in turn induce senescence. However, their role in fibroblasts senescence in COPD is unknown. OBJECTIVES: The aim of this study was to analyze the role of sPLA2 in pulmonary fibroblast senescence. METHODS: Fibroblasts were isolated from patients with COPD and control subjects, and senescence markers and inflammatory profile was analyzed. sPLA2 levels were quantified in serum of COPD and controls. MAIN RESULTS: In comparison with non-smokers and smoker controls, senescent lung COPD fibroblasts exhibited a higher mRNA and protein expression of the sPLA2 isoform XIIA and of syndecan 4 (one of its receptors). sPLA2 XIIA induced in turn senescence of non-senescent pulmonary fibroblasts via a pathway involving consecutively syndecan 4, activation of MAPK and p-serine 727 STAT-3, increased mitochondrial ROS production, and activation of AMPK/p53. This pathway was associated with a specific inflammatory secretome (IL-10, IL-12 and TNFα), globally suggesting occurrence of a mitochondrial damage-induced senescence. COPD fibroblasts were more susceptible to this sPLA2 XIIA effect than cells from controls subjects. sPLA2 XIIA levels were significantly higher in serum from COPD patients as compared to controls. CONCLUSION: sPLA2 XIIA is involved in senescence in COPD and could be a potential target to dampen this process.

Heparin-like polymer improved healing of gastric and colic ulceration.

A family of chemically substituted biopolymers has been developed to protect and stabilize heparin binding growth factors and was shown to enhance tissue repair in various in vivo models. One of these compounds, a dextran derivative named RGTA11, was tested for its ability to treat acute gastritis and colic ulceration models induced by ethanol and acid. RGTA was not efficient in reducing nor in protecting against gastric acidic secretion compared to EGF. Ethanol gastritis measured by the alteration score of the injured mucosa was reduced by 56% with the oral administration of RGTA at doses of 100 microg/kg (p < 0.01). A similar effect was obtained by PGE2 at a similar dose. Alterations of the colic mucosa were reduced after 72 h by 75% after oral administration of RGTA11. RGTA presents both anti-inflammatory and tissue repair activities mediated by growth factor protection. These two properties would be beneficial for digestive ulcer treatment. The results presented here provide evidence for these effects.