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Copyright of Revista de la Asociación Colombiana de Dermatología y Cirugía Dermatológica is the property of Asociacion Colombiana de Dermatologia y Cirugia Dermatologica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

OBJECTIVE: To investigate the effects of dexmedetomidine (Dex) treatment administered at various times on acute lung injury (ALI). MATERIALS AND METHODS: Thirty Wistar rats were randomly divided into five groups (n = 6/group). Lipopolysaccharide (LPS) was intraperitoneally injected into the rats in the LPS, Dex1, Dex2, and Dex3 groups to induce ALI, while the control group (C) was left untreated. Rats in the Dex1 group were intraperitoneally administered with 50 µg/kg Dex 30 minutes before modeling. Rats in the Dex2 group were injected with 25 µg/kg Dex 30 minutes before modeling and two hours after. Rats in the Dex3 group received 50 µg/kg Dex two hours after modeling. The animals in the C and LPS groups were given an equal volume of saline. The wet-to-dry (W/D) weight ratio of the rats' lungs was calculated, and pathological alterations in lung tissues were observed. The concentrations of inflammation-related factors and the expression of Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and matrix metallopeptidase 9 (MMP9) were measured. RESULTS: The W/D ratio, expression of inflammatory factors, and expression of JAK1, STAT3, and MMP9 were significantly increased in the ALI rats (p < 0.05) compared with the C group. The level of anti-inflammatory factors in the Dex-treated groups was also significantly increased compared with the LPS group (p < 0.05). The concentration of anti-inflammatory factors in the Dex2 group was significantly higher than that recorded in the Dex1 and Dex3 groups (p < 0.05). CONCLUSIONS: Dex treatment administered at different times protects rats against LPS-induced ALI to varying degrees. The protective effects of Dex were most robust when administered both before and after LPS stimulation. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) 2 plays pivotal roles in signaling by several cytokine receptors. The mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the mutant would be ideal for treating these pathologies by sparing essential JAK2 functions. We characterize inhibitory strategies for JAK2 V617F and assess their effect on physiologic signaling by distinct cytokine receptors. Through structure-guided mutagenesis, we assessed the role of key residues around F617 and used a combination of cellular and biochemical assays to measure the activity of JAKs in reconstituted cells. We also assessed the effect of several specific JAK2 V617F inhibitory mutations on receptor dimerization using the NanoBiT protein complementation approach. We identified a novel Janus kinase homology 2 (JH2) αC mutation, A598F, which is suggested to inhibit the aromatic stacking between F617 with F594 and F595. Like other JAK2 V617F inhibitory mutations, A598F decreased oncogenic activation and spared cytokine activation while preventing JAK2 V617F–promoted erythropoietin receptor dimerization. Surprisingly, A598F and other V617F-inhibiting mutations (F595A, E596R, and F537A) significantly impaired IFN-γ signaling. This was specific for IFN-γ because the inhibitory mutations preserved responses to ligands of a series of receptor complexes. Similarly, homologous mutations in JAK1 prevented signaling by IFN-γ. The JH2 αC region, which is required for JAK2 V617F hyperactivation, is crucial for relaying cytokine-induced signaling of the IFN-γ receptor. We discuss how strategies aiming to inhibit JAK2 V617F could be used for identifying inhibitors of IFN-γ signaling. [ABSTRACT FROM AUTHOR]