curcumin and Pneumonia--Staphylococcal

Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 μL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.

Topics: Alleles; Animals; Curcumin; Genetic Predisposition to Disease; Genetic Variation; Humans; Lung Injury; Mice; Mice, Transgenic; Pneumonia, Staphylococcal; Pulmonary Surfactant-Associated Protein B; Staphylococcus aureus

α-hemolysin (Hla) is a self-assembling extracellular protein secreted as a soluble monomer by most Staphylococcus aureus strains and is an essential virulence factor for the pathogenesis of various S. aureus infections. Here, we show that curcumin (CUR), a natural compound with weak anti-S. aureus activity, can inhibit the hemolysis induced by Hla. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were further employed for the Hla-CUR complex to determine the mechanism of such inhibition. The analysis of this combined approach indicated that the direct binding CUR to Hla blocks the conformational transition of Hla from the monomer to the oligomer, leading to an inhibition of Hla hemolytic activity. We also found that the addition of CUR significantly attenuated Hla-mediated injury of human alveolar cell (A549) co-cultured with S. aureus. The in vivo data further demonstrated that treatment with CUR protects mice from pneumonia caused by S. aureus, including methicillin-resistant strains (MRSA). These findings suggest that CUR inhibits the pore-forming activity of Hla through a novel mechanism, which would pave the way for the development of new and more effective antibacterial agents to combat S. aureus pneumonia.

Topics: Animals; Anti-Bacterial Agents; Bacterial Toxins; Curcumin; Female; Hemolysin Proteins; Hemolysis; Methicillin Resistance; Mice; Mice, Inbred C57BL; Pneumonia, Staphylococcal; Protective Agents; Staphylococcus aureus; Virulence Factors

Curcumin has remarkable anti-inflammatory and antioxidant properties. However, its effects on bacterium-induced acute lung injury (ALI) are not fully understood.. To investigate the protective effects of curcumin on a mouse model of S. aureus-induced ALI.. Mice were pretreated with intraperitoneal injection of curcumin or vehicle 2 h before Staphylococcus aureus instillation. The survival rate and bacterial burden after infection were recorded. Mice were sacrificed for the analyses of severity of pneumonia, integrity of lung barrier, disorder of coagulation cascades and extent of inflammation 12 h postinfection. The production of proinflammatory cytokines and chemokines in the lung and bronchoalveolar lavage fluid was detected.. Pretreatment with curcumin markedly attenuated S. aureus-induced pneumonia, barrier disruption, lung edema and vascular leakage. Activation of plasminogen activator inhibitor-1 and infiltration of neutrophils were reduced by curcumin, together with lower levels of proinflammatory cytokines and chemokines.. Curcumin can alleviate S. aureus-induced ALI through multiple pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Disease Models, Animal; Female; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Pneumonia, Staphylococcal; Staphylococcus aureus