| Pasteurella multocida pneumonia is very common in veterinary medicine thatremains associated with high morbidity and mortality. To address the important globalunmet need for treatment, several new antibiotics were developed over the last severaldecades, yet pneumonia mortality has not decreased. One explanation for thepersistent adverse outcomes for pneumonia is the pathogen-initiated inflammatoryresponse that can spiral out of control and lead to acute lung injury (ALI) or the acuterespiratory distress (ARDS). Whereas pathogen-mediated inflammation is essentialfor host defense, unrestrained activation of leukocytes and lung tissue resident cellscan lead to excess tissue injury, finally lead to multiple organ dysfunction, whichcause great damage to the health of humans and animals. Due to the side effects andthe increasing of antibiotic resistance in bacteria of traditional drugs, we are aiming atsearching drugs with better curative effect and less side effects to treat inflammation.There are many advantages about traditional Chinese medicine such as less sideeffects and wider sphere of action. The effect of certain traditional Chinese medicineon inflammation has been a topic of recent interest.Linalool, is an abundant naturally occurring chains of terpene alcohol in nearlyall the natural fragrance. It has been showed anti-inflammatory effects inlipopolysaccharide-induced lung injury model, but the detailed mechanism againstPasteurella multocida (P. multocida) pneumonia of linalool is unclear.In the present research, linalool may modulate the oxidative stress pathway inorder to protect against lung inflammation induced by P. Multocida both in vitro andin vivo. First, different concentrations of linaloll were added to A549cells toinvestigate if linalool could activate Nrf-2. EMSA was used to prove the above result. Then, to further verify the involvement of Nrf-2in P. multocida-induced cytokinesexpression, Nrf-2gene was knocked down using its specific siRNA to examinecytokines expression. On this basis, a mouse model of P. multocida-inducedGram-negative bacterial pneumonia was established and the treatment effect oflinalool on mice with pneumonia was tested. Lungs were collected for assayingwet-to-dry weight (W/D) ratios, myeloperoxidase (MPO), superoxide dismutase(SOD), reactive oxygen species (ROS), cytokine levels and histological change.The results showed that after treatment with linalool, the translocation of Nrf-2from cytoplasm into nucleus increased in a dose-dependent manner. Expression ofHO-1, a downstream molecule of Nrf-2, also increased following linalool treatment.Furthermore, pro-inflammatory cytokines production (including TNF-α and IL-6) wassignificantly increased in P. multocida challenged cells, while P. multocida-challengedcells further treated with linalool had lower concentrations of pro-inflammatorycytokines in the supernatants of cells. The beneficial effect of linalool treatment wasagain lost when P. multocida-challenged cells were treated with a combination oflinalool and Nrf-2siRNA. Collectively, these data indicate that Nrf-2is an importanttranscriptional regulator for P. multocida induced pro-inflammatory cytokinesexpression in A549cells and further supports the hypothesis that the action of linaloolis dependent on Nrf-2. In P. multocida-induced Gram-negative bacterial pneumonia,linalool could lead to the generation of antioxidant enzymes that might provideresistance against the development of lung inflammation, neutrophils infiltration andpro-inflammatory cytokines release. In conclusion, these results suggest that linaloolpotentially decreases the inflammation via modulating the oxidative stress pathway,and may be a therapeutic agent against inflammatory disease. |
