RESUMEN
Purpose: Here, we studied the pharmacological effect of P22077 on airway inflammation induced by lipopolysaccharide and cigarette smoke and explored the therapeutic mechanism of P22077 in COPD model RAT. Patients and Methods: The COPD model was established by lipopolysaccharide combined with fumigation; animals were treated with vehicle or P22077. Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for analysis. Results: Our results showed that P22077 treatment significantly improved the airway inflammation of COPD model RAT and reduced the recruitment of leukocytes in BALF, and hypersecretion of interleukin-18 (IL-18), interleukin-1ß (IL-1ß) in BALF and serum. H&E staining showed that P22077 treatment could effectively reduce emphysema, immune cell infiltration and airway wall destruction. PAS staining showed that The proliferation of cup cells in the airway wall and the number of bronchial cup cells were significantly reduced in rats treated with P22077. In addition, we found that P22077 treatment suppressed the generation of the NLRP3/ASC/Caspase 1 inflammasome complex to inhibit the inflammatory response caused by IL-1ß and IL-18. Conclusion: Conclusion: P22077 inhibits expression of NLRP3 pathway-related inflammatory factors and proteins and reduces the airway inflammatory response and inflammatory cell aggregation in COPD rats. The underlying mechanism may be related to the down-regulation of NLRP3 inflammatory vesicle signaling pathway expression.
Asunto(s)
Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad Pulmonar Obstructiva Crónica , Tiofenos , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18/metabolismo , Interleucina-18/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Lipopolisacáridos , Pulmón/metabolismo , Inflamación/complicaciones , Líquido del Lavado Bronquioalveolar , Interleucina-1beta/metabolismoRESUMEN
Asthma is a chronic inflammatory disease of the respiratory system. Maresin-2 (MaR2) is biosynthesized from docosahexaenoic acid (DHA) by macrophages, display strong anti-inflammatory and pro-resolving activity. To investigate the therapeutic effect and mechanism of MaR2 on asthmatic mice induced by ovalbumin (OVA) in conjunction with the adjuvant aluminum hydroxide. Twenty four female BALB/c mice were randomly divided into control, OVA, OVA + MaR2, and OVA + dexamethasone (Dexa) groups. MaR2 or Dexa were given as a treatment for OVA-induced asthma. Serum, bronchoalveolar alveolar lavage fluid (BALF) and lung tissue were collected for further analysis. The Pathological changes of lung tissue, proportion of inflammatory cells in BALF, levels of inflammatory cytokines in BALF or serum, oxidative stress indices, and the protein concentration of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 in lung tissues were evaluated. Compared with the OVA group, both OVA + MaR2 and OVA + Dexa group had reduced inflammation and mucus secretion in lung tissue, number of inflammatory cells in BALF, levels of related inflammatory cytokines in serum or BALF, and expressions of ASC, MPO, Ly-6G, ICAM-1, NLRP3 and Caspase-1 proteins in lung tissue. In addition, the oxidative stress was alleviated as indicated by decreased MDA, and elevated SOD and GSH. MaR2 has an obvious protective effect on OVA-induced bronchial asthma in mice, in a similar manner as Dexa. The mechanism may be related to the inhibition of the Th2 type immune response, the NLRP3 inflammasome activation and oxidative stress.
Asunto(s)
Asma , Inflamasomas , Animales , Líquido del Lavado Bronquioalveolar , Caspasas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Femenino , Inmunidad , Inflamasomas/metabolismo , Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Pulmón , Ratones , Ratones Endogámicos BALB C , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ovalbúmina , Estrés OxidativoRESUMEN
We sought to assess the protective effect of different doses of Fingolimod (FTY720) in a rat model of acute lung injury (ALI) induced by intratracheal instillation of lipopolysaccharide (LPS) and explored the underlying mechanisms. The ALI model was established in rats and different doses of FTY720 (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, or 2 mg/kg) were injected intraperitoneally. Lung computed tomography and blood gas analyses were performed at 6 h, 24 h, and 48 h after intraperitoneal injection, and the lung tissues were extracted to prepare paraffin sections for histopathological examination. The levels of inflammatory cytokines (TNF-α, IL-6, and IL-1ß) were detected by ELISA, and the expressions of inflammatory pathway proteins in each group were measured by Western blot analysis. A single intraperitoneal injection of FTY720 inhibited LPS-induced NF-κB activation, reduced the level of inflammatory cytokines, and decreased the infiltration of inflammatory cells. Moreover, it alleviated lung tissue injury, as shown by marked attenuation of pulmonary oedema and improved arterial partial pressure of oxygen (PaO2) and the general condition of ALI rats. In conclusion, our results demonstrate the protective effect of FTY720 against LPS-induced ALI. The underlying mechanism of the protective effect may involve inhibition of LPS-induced activation of NF-κB and regulation of the inflammatory pathway to alleviate barrier dysfunction of alveolar capillaries.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Análisis de los Gases de la Sangre , Barrera Alveolocapilar/efectos de los fármacos , Citocinas/sangre , Relación Dosis-Respuesta a Droga , Clorhidrato de Fingolimod/administración & dosificación , Inmunosupresores/administración & dosificación , Inyecciones Intraperitoneales , Lipopolisacáridos , Pulmón/patología , Masculino , FN-kappa B/efectos de los fármacos , Oxígeno/sangre , Edema Pulmonar/prevención & control , Ratas , Ratas Sprague-Dawley , Tomografía Computarizada por Rayos XRESUMEN
Asthma is a chronic inflammatory disease that cannot be cured. Maresin 1 (MaR1) is a specific lipid synthesized by macrophages that exhibits powerful anti-inflammatory effects in various inflammatory diseases. The goal of this study was to evaluate the effect of MaR1 on allergic asthma using an ovalbumin- (OVA-) induced asthma model. Thirty BALB/c mice were randomly allocated to control, OVA, and MaR1 + OVA groups. Mice were sacrificed 24 hours after the end of the last challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for further analysis. Western blotting was used to measure the protein level of IκBα, the activation of the NF-κB signaling pathway, and the expression of NF-κB downstream inflammatory cytokines. Quantitative real-time polymerase chain reactions (qRT-PCRs) were used to evaluate the expression levels of COX-2 and ICAM-1 in lung tissues. We found that high doses of MaR1 were most effective in preventing OVA-induced inflammatory cell infiltration and excessive mucus production in lung tissue, reducing the number of inflammatory cells in the BALF and inhibiting the expression of serum or BALF-associated inflammatory factors. Furthermore, high-dose MaR1 treatment markedly suppressed the activation of the NF-κB signaling pathway, the degradation of IκBα, and the expression of inflammatory genes downstream of NF-κB, such as COX-2 and ICAM-1, in the OVA-induced asthma mouse model. Our findings indicate that MaR1 may play a critical role in OVA-induced asthma and may be therapeutically useful for the management of asthma.