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Neonatal Streptococcus Pneumoniae pneumonia induces airway SMMHC expression through HMGB1/TLR4/ERK
Yuanyuan Li1, Ziyao Guo1, Guangli Zhang1
1Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, China International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400014, China.
Background:
Our previous study showed that neonatal S. pneumoniae pneumonia promoted airway smooth muscle myosin heavy chain (SMMHC) expression and AHR development. Researches demonstrated HMGB1, TLR4 and ERK are involved in smooth muscle contractile protein expression, so we hypothesis that HMGB1/TLR4/ERK pathway participated in airway SMMHC overexpression in neonatal S. pneumoniae pneumonia model.
Method:
Neonatal (1-week-old) BALB/c mice were intranasal inoculated with D39 to establish non-lethal S. pneumoniae pneumonia model. TLR4 was inhibited 2 weeks after infection with TLR4 specific inhibitor (TAK-242). Five weeks after infection, the bronchoalveolar lavage fluid (BALF) and lungs of neonatal S. pneumoniae pneumonia and mock infection mice with or without TLR4 inhibition were collected to assess the expressions of HMGB1, TLR4 and p-ERK1/2. Airway Hyperresponsiveness (AHR) of the three groups was determined by whole-body plethysmograph.
Results:
Our results demonstrated that neonatal S. pneumoniae pneumonia promoted HMGB1/TLR4 production, SMMHC expression and AHR development significantly, with ERK1/2 phosphorylation decreased remarkably. TLR4 inhibition after pneumonia significantly increased ERK1/2 phosphorylation, reversed airway SMMHC overexpression and alleviated AHR.
Conclusion:
Neonatal S. pneumoniae pneumonia promotes airway SMMHC expression and AHR through HMGB1/TLR4/ERK.
Insights
Neonatal pneumonia from Streptococcus pneumoniae increases airway smooth muscle myosin heavy chain (SMMHC) and airway hyperresponsiveness (AHR). Targeting the HMGB1/TLR4/ERK pathway can reverse these effects.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cellular Biology
Background:
- Neonatal Streptococcus pneumoniae pneumonia is linked to airway smooth muscle myosin heavy chain (SMMHC) overexpression and airway hyperresponsiveness (AHR).
- The HMGB1/TLR4/ERK pathway is implicated in smooth muscle contractile protein expression.
Purpose of the Study:
- To investigate the role of the HMGB1/TLR4/ERK pathway in SMMHC overexpression and AHR development in a neonatal S. pneumoniae pneumonia model.
Main Methods:
- A neonatal mouse model of S. pneumoniae pneumonia was established.
- Toll-like receptor 4 (TLR4) was inhibited using TAK-242.
- Expressions of HMGB1, TLR4, p-ERK1/2, and SMMHC were assessed, along with AHR measurements.
Main Results:
- S. pneumoniae pneumonia significantly increased HMGB1/TLR4 production, SMMHC expression, and AHR, while decreasing ERK1/2 phosphorylation.
- TLR4 inhibition notably enhanced ERK1/2 phosphorylation, reversed SMMHC overexpression, and alleviated AHR.
Conclusions:
- Neonatal S. pneumoniae pneumonia promotes airway SMMHC expression and AHR via the HMGB1/TLR4/ERK pathway.
- Targeting TLR4 offers a potential therapeutic strategy for mitigating airway hyperresponsiveness in neonatal pneumonia.
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