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Background and Purpose Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073. Experimental Approach We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, P seudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P . aeruginosa LPS. Key Results In contrast to azithromycin, CSY0073 did not inhibit the growth of P . aeruginosa, S taphylococcus aureus or H aemophilus influenzae and had no effect on an established P . aeruginosa biofilm. Bronchoalveolar lavage ( BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg−1, i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P . aeruginosa LPS. Conclusions and Implications Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases. [ABSTRACT FROM AUTHOR]

In this paper we have studied the combined effects on platelet activation, of two polymorphonuclear neutrophil (PMN)-derived agonists, namely platelet-activating factor (PAF) and cathepsin G (Cat.G), used at threshold concentrations. Our results showed that the order of agonist addition was a determinant factor since the addition of Cat.G prior to PAF induced a full platelet activation while the reverse combination had no effects. The successive challenge of platelets by Cat.G and then PAF induced a strong aggregation accompanied by an enhancement of alpha and dense granule secretion. The observed phenomenon was also dependent on the time interval between agonist addition. It was significant at 30 s (P less than 0.05) and plateaued over 1-2 min. Platelet activation resulting from the combination Cat.G-PAF can be described as a function of PAF concentrations, the synergism being significant between 10 nM and 1 microM. The mechanism by which Cat.G primes platelets remains to be elucidated. However, some points have been examined and have led us to conclude that an increase in expression and/or affinity of PAF receptors, [Ca2+]i movements, protein kinase C activation and phospholipase A2 pathway are not involved. Whatever the biochemical mechanism underlying this synergism which involved PMN and platelets, it may constitute a link between the inflammatory and haemostatic processes in response to tissue damage.

A new type of congenital platelet dysfunction was found in a young woman presenting a life-long bleeding disorder. The known types of thrombopathia and von Willebrand's disease were excluded by appropriate investigations. The platelets were morphologically normal, underwent normal shape change and contraction and synthesized thromboxane A2 (TXA2) normally. The release reaction was abnormal and the aggregation response to ADP, adrenalin, collagen, thrombin, sodium arachidonate and vasopressin was depressed due to decreased sensitivity of the platelets to prostaglandin endoperoxides and TXA2. Platelet cAMP content was increased.