R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

Abstract

Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/ MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.

Single Immunoglobulin Interleukin-1 Receptor-Related Molecule Impairs Host Defense during Pneumonia and Sepsis Caused by <b><i>Streptococcus Pneumoniae</i></b>

“…Lungs, blood, spleens, and livers were harvested 6, 24, or 48 h postinfection for quantitative bacterial cultures as described (n = 8 or 16 per group at each time point) [23,24]. Neutrophil counts in bronchoalveolar lavage (BAL) fluid were determined as described [25]. In separate studies, mice were followed for 4 days and survival was monitored at least every 12 h (n = 20 per group).…”

Bacterial meningitis: an update of new treatment options

“…Seliciclib was also effective in a Str. pneumoniae pneumonia model [204]. However, it has cytostatic properties and is being studied for small cell lung cancer, lymphomas and other malignancies [205].…”

“…However, it has cytostatic properties and is being studied for small cell lung cancer, lymphomas and other malignancies [205]. Whether it is suitable for immunomodulation in bacterial infections will depend on the severity of the immune defect induced by this compound [204].…”

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

“…Several mouse models of lung inflammation or injury were efficiently treated with roscovitine by intraperitoneal administration: bleomycin-induced lung injury [74], lipoteichoic acid and Streptococcus pneumonia -induced lung inflammation [75], mechanical ventilation -induced lung injury [76]. Furthermore, roscovitine has been evaluated in phase IIa clinical trials against NSC lung cancer, where a substantial increase in overall survival was observed (388 versus 218 days in the placebo arm), despite no difference in progression free survival [68].…”

“…Inhibition of the NFκB pathway by CR8, an analogue of roscovitine, was also observed in chronic lymphocytic leukemia cells [158]. The anti-inflammatory effect of roscovitine via enhanced apoptosis of neutrophils was confirmed in a zebrafish inflammatory model [159, 160], a mouse model with pulmonary inflammation induced by Streptococcus pneumoniae and lipoteichoic acid (a pro-inflammatory constituent of gram positive bacteria) [75], a mouse model of ventilator-induced lung injury [76] and an experimental mouse model of pneumococcal meningitis [161]. It was also shown that roscovitine, by inhibiting CDK2 and CDK5, blocks endothelial activation and leucocyte/endothelial cell interactions, contributing to the anti-inflammatory effect [162].…”