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Cyclin-dependent kinase inhibitor r-roscovitine reduces lipoteichoic acid lung inflammation and improves the resolution of antibiotic-treated Streptococcus pneumoniae pneumonia
Critical Care volume 13, Article number: P39 (2009)
Streptoccocus pneumoniae pneumonia remains associated with high morbidity and mortality. Antibiotic treatment frequently is insufficient in limiting lung damage due to inflammation. Therefore, additional treatment strategies are needed. The drug r-roscovitine, a cyclin-dependent kinase (CDK) inhibitor, was demonstrated to reduce inflammation in several models of inflammation.
We studied the potential of r-roscovitine to modulate host defense during sterile inflammation and bacterial infection of the lung.
Isolated neutrophils were treated with 20 μM r-roscovitine and CDK and caspase 3 activity were determined by western blot analysis. Sterile lung inflammation was induced by intranasal administration of 100 μg lipoteichoic acid (LTA), a prominent cell wall component of Gram-positive bacteria. Simultaneously 70 mg/kg r-roscovitine or vehicle was injected intraperitoneally. Twenty-four hours later bronchoalveolar lavage (BAL) was performed and differential cell counts were determined. Bacterial pneumonia was induced by inoculation of 5 × 104 CFU S. pneumoniae. r-roscovitine (70 mg/kg) or vehicle was administered 24 hours later in combination with antibiotic therapy (ceftriaxon; 20 mg/kg). Mice were sacrificed after 48 hours. In a second experiment, mice were infected and treated at 24 and 72 hours and sacrificed 96 hours post infection.
r-roscovitine treatment significantly reduced phosphorylated CDK substrate and increased cleaved caspase 3 levels in isolated neutrophils. During LTA-induced lung inflammation, r-roscovitine treatment significantly reduced the amount of PMNs in the BAL fluid and cytokines in lung homogenates. After 48 hours of bacterial pneumonia, r-roscovitine-treated animals displayed enhanced pulmonary bacterial outgrowth. Cytokine production and lung damage scores were higher in the r-roscovitine-treated group as compared with vehicle. Interestingly, when studying the animals at 96 hours post infection, r-roscovitine treatment resulted in lower bacterial outgrowth and chemokine levels in the lung.
With this study, we reproduced earlier findings that r-roscovitine treatment reduces CDK activity and induces apoptosis in neutrophils; we demonstrated that r-roscovitine diminishes inflammatory responses in sterile inflammation; and we found that r-roscovitine treatment in bacterial pneumonia is detrimental early in infection but beneficial at later time points. We believe that the negative effect of r-roscovitine reflects the importance of neutrophil antibacterial defense early in infection. Yet, during resolution of infection, apoptosis of neutrophils induced by r-roscovitine could present a way of damage control as opposed to unwanted side effects of neutrophil function.
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Hoogendijk, A., Roelofs, J., van Lieshout, M. et al. Cyclin-dependent kinase inhibitor r-roscovitine reduces lipoteichoic acid lung inflammation and improves the resolution of antibiotic-treated Streptococcus pneumoniae pneumonia. Crit Care 13, P39 (2009). https://doi.org/10.1186/cc8095
- Streptococcus Pneumoniae
- Post Infection
- Lung Inflammation
- Bacterial Pneumonia
- Intranasal Administration