【Abstract】Objective To investigate the mechanism of Xuanfei Jiedu Formula on multi-drug resistant Pseudomonas aeruginosa pneumonia. Methods In addition to the blank control group, the other groups used tracheal intubation to establish a rat model of MDR-PA (9×108 CFU/ML, 0.5 mL) pneumonia, and were randomly divided into the model group, Xuanfei Jiedu formula low dose group, Xuanfei Jiedu formula medium dose group, Xuanfei Jiedu formula high dose group, and Imipenem cilastatin group. After 1 day of modeling, 1.725g/kg/d, 3.45g/kg/d and 6.9g/kg/d of XFJDF were given by gavage in the low, medium and high dose groups respectively, 410 mg/kg/d of IPM was given by intraperitoneal injection in the imipenem cistatin group, saline was given by gavage in the blank control group and the model group; 2 times/day for 7 days. We observed the state changes, body weight changes, and wet-to-dry weight ratio (W/D) of the lung tissues of the rats, the histopathological changes of the lung tissues in each group under the light microscope using Hematoxylin-Eosin staining (HE) , detected the serum of the rats in each group by using enzyme immunosorbent assay (ELISA) to detect the interleukin-1β, interleukin-6, tumor necrosis factor-α (TNF-α) inflammatory factors , the content of reduced glutathione (GSH) and the activity of myeloperoxidase (MPO) were detected by colorimetric assay, the content of myeloperoxidase (MPO) was detected by TBA.The localization and semi-quantitative observation of TLR4, Myd88, and NF-κB p65 proteins in lung tissues were carried out by immunohistochemistry (IHC).Real-time fluorescence quantitative PCR (RT-qPCR) and protein immunoblotting (Western Blot) were used to detect the expression levels of TLR4, Myd88, NF-κB mRNA and protein in the lung tissues of rats in each group. Results Compared with the Control group, rats in the Model group showed delayed response, increased respiratory rate and murmur, different degrees of chills, decreased diet and water intake, weight loss; the W/D of the lung tissue (P<0.01) was significantly higher, and the alveolar cavities and peribronchioles of the lung tissue contained a large number of inflammatory cell infiltration, some of the alveolar walls showed fracture and fusion to form an airspace with inflammatory exudation, while the interstitial spaces of the lung tissue showed a large number of inflammatory cell infiltration. Inflammatory exudation, interstitial thickening and localized pulmonary fibrosis were observed. Serum levels of IL-1β, TNF-α and TGF-β were significantly elevated (P < 0.01) and the levels of MDA, MPO and GSH were increased (P<0.01) the expression of mRNA and protein of TLR4, Myd88, and NF-κB was significantly elevated (P<0.01) in the lungs. Compared with the Model group, all the treatment groups of the intervention group improved the general state of MDR-PA rats, which showed significantly better mental state, enhanced response sensitivity, increased body weight, decreased lung W/D (P<0.01), significantly improved pathological injury of lung tissues, significantly decreased levels of TNF-α, TGF-β and MDA, increased levels of GSH in serum (P < 0.01); except for the Except for the XFJDF low-dose group, the serum levels of IL-1β and MPO activity were significantly reduced (P<0.01); the mRNA and protein expression levels of TLR4, Myd88 and NF-κB were significantly reduced in the lung tissues (P< 0.01, P< 0.05), the most significant reduction was observed in the XFJDF high-dose group and the IPM group. Conclusion Xuanfei Jiedu formula significantly improved the general status, body weight, lung W/D and lung histopathology, reduced inflammation and oxidative stress in MDR-PA rats, its mechanism may be related to the inhibition of the TLR4/Myd88/NF-κB pathway expression in the lungs by Xuanfei Jiedu formula.