| Background: Asthma is a common non-infectious chronic airway disease characterized by chronic airway inflammation,airway remodeling and airway hyperresponsiveness.Among them,chronic airway inflammation is considered to be the basic pathological change of asthma.Heat shock protein 90(HSP90)plays an important role in respiratory diseases.Proteomics studies of HSP90 suggest that the complexity of HSP90 role and function depends on its post-translational modification.HSP90 is an important non-histone substrate of histone deacetylase 6(HDAC6).HDAC6 plays a role in a variety of diseases by regulating the acetylation level of HSP90.Our previous study found that the expression of HDAC6 in the lung tissue of asthmatic mice was increased,and the specific HDAC6 inhibitor Tubastatin A Hcl could reduce airway inflammation in asthmatic mice.Objective: To review the research status of HSP90 in respiratory diseases.The research hotspots and trends of HSP90 in this field are airway inflammation and histone deacetylation modification.To further investigate the effect of specific HDAC6 inhibitor Tubastatin A Hcl on airway inflammation in asthmatic mice and the molecular mechanism of Tubastatin A Hcl regulating HDAC6/HSP90/IKK/NF-κB signaling pathway in the treatment of airway inflammation in asthmatic mice.Methods:Part I: To analyze the research hotspots and trends of HSP90 in respiratory diseases.Literature search was conducted using the Web of Science core collection to collect research articles on HSP90 in respiratory diseases from 2010 to 2021.VOSviewer and Cite Space software were used for bibliometric analysis.Part II : Tubastatin A Hcl regulates HDAC6/HSP90/IKK/ NF-κB signaling pathway to treat airway inflammation in asthmatic mice.According to the results of the first part of the bibliometric analysis,airway inflammation and HDAC inhibitors are the current research hotspots of HSP90 in respiratory diseases.The mouse model of asthma was further constructed to investigate the effect of specific HDAC6 inhibitor Tubastatin A Hcl on airway inflammation in asthmatic mice and the molecular mechanism of Tubastatin A Hcl regulating HDAC6/HSP90/IKK/NF-κB signaling pathway in the treatment of airway inflammation in asthmatic mice.6-8 weeks SPF female BALB/C mice were randomly divided into 4 groups: normal control group,asthma group,dexamethasone group and Tubastatin A Hcl group,with 6mice in each group.Ovalbumin(OVA)sensitization and ova challenge were used to establish a mouse model of asthma.Airway resistance was measured to assess airway responsiveness.HE,AB-PAS and Masson staining were used to observe airway inflammatory cell infiltration,mucus secretion,airway epithelial goblet cell proliferation and collagen deposition around the airway in each group.The expression and distribution of p-IKK and p-NF-κB in lung tissue were detected by immunohistochemical staining.Western blot was used to detect the expression levels of HDAC6,p-IKK,p-NF-κB,IKK and NF-κB in lung tissue of mice in each group.The levels of HSP90 acetylation in lung tissues were detected by immunoprecipitation.Results:Part I: To analyze the research hotspots and trends of HSP90 in respiratory diseases.For the research of HSP90 in respiratory diseases,a total of 637 publications were screened,11184 were cited after removing self-citation,the citation frequency was 14029 times after removing self-citation,the average citation frequency was 23.86,and the H index was 57.The citation report results show a surge in the number of publications in2021.HSP90,expression,and activation were three keywords that appeared frequently.Inflammation and HDAC inhibitors are emerging hot keywords in recent years.HSP90 and NF-κB signaling pathway have become a research hotspot in recent years.Part II : Tubastatin A Hcl regulates HDAC6/HSP90/IKK/ NF-κB signaling pathway to treat airway inflammation in asthmatic mice.1.Establishment of asthma mouse model and detection of airway inflammation: compared with the normal control group,the airway hyperresponsiveness of asthma group mice was significantly increased;Compared with the asthma group,the airway hyperresponsiveness of dexamethasone group and Tubastatin A Hcl group was significantly decreased.HE,ABPAS and Masson staining showed that compared with the normal control group,the asthma group had a large number of inflammatory cell infiltration around the airway,mucus secretion in the airway,obvious proliferation of airway epithelial goblet cells,and increased deposition of subepithelium collagen fibers.Compared with the asthma group,the levels of airway inflammation,airway epithelial goblet cell proliferation and collagen deposition around the airway were significantly decreased in the dexamethasone group and Tubastatin A Hcl group.2.HDAC6 expression level and HSP90 acetylation level in lung tissue of mice: compared with the normal control group,the expression level of HDAC6 in lung tissue of mice in the asthma group was increased.The expression level of HDAC6 in lung tissue of mice was decreased after Tubastatin A Hcl intervention.Compared with the normal control group,the acetylation level of HSP90 in the lung tissue of the asthma group was decreased.HSP90 acetylation was increased in lung tissues of mice treated with Tubastatin A Hcl.3.IKK and NF-κB phosphorylation levels in lung tissue of mice: compared with normal control group,IKK phosphorylation levels in lung tissue of mice of asthma group increased and NF-κB phosphorylation levels increased;The phosphorylation levels of IKK and NF-κB were decreased after Tubastatin A Hcl intervention.Conclusion: Airway inflammation and histone deacetylation modification are the current research hotspots and trends of HSP90 in respiratory diseases.The specific HDAC6 inhibitor Tubastatin A Hcl can effectively alleviate airway inflammation in asthmatic mice,and its mechanism may be related to the up-regulation of HSP90 acetylation level by Tubastatin A Hcl,thereby inhibiting IKK/NF-κB signaling pathway. |
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