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Updated: Feb 7, 2026
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis
Qiufang Deng1,2, Ting Zhao1, Baihong Pan1,2
1Department of Surgery, North Campus Research Complex, University of Michigan, Rm 363N, Bldg 26, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Abstract:
We have found earlier that Tubastatin A (TubA), a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival in a mouse model of lethal cecal ligation and puncture (CLP)-induced sepsis. However, the underlying mechanisms have not been fully established. This study sought to test the hypothesis that TubA could affect both lung and splenic functions. C57BL/6J mice were subjected to CLP, and randomized to receive either TubA (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO), or DMSO alone, 1 h following CLP. Sham animals acted as control. Twenty-four hours later, lung tissue was harvested for pathological examination, and splenic tissue was harvested for bacterial colonization. In a parallel study, the spleen was collected 48 h following CLP, and single cell suspension was prepared. Splenocytes then underwent flow cytometry to analyze the immune cell population. RAW264.7 macrophages were treated with lipopolysaccharide (LPS) with or without the presence of TubA (10 μM) at 37 °C for 3 h to assess the effect on macrophage phagocytosis. We found that acute lung injury secondary to lethal sepsis was attenuated by TubA. Treatment with TubA restored the percentage of B lymphocytes, and significantly increased percentages of innate immune cells and macrophages compared to the vehicle-treated CLP group. Moreover, TubA significantly decreased the bacterial load in the spleen, and improved the phagocytic ability of RAW264.7 murine macrophages in vitro. Such findings may help to explain the beneficial effects of TubA treatment in a model of lethal sepsis, as previously reported.
Insights
Tubastatin A (TubA) treatment improved survival in a mouse model of sepsis by reducing lung injury and bacterial load. It also enhanced immune cell function and macrophage phagocytosis.
Area of Science:
- Immunology
- Pharmacology
- Pathology
Background:
- Sepsis, a life-threatening organ dysfunction caused by dysregulated host response to infection, remains a major global health challenge.
- Histone deacetylase 6 (HDAC6) inhibition with Tubastatin A (TubA) has shown promise in improving survival in preclinical sepsis models.
- The precise mechanisms by which TubA exerts its beneficial effects, particularly on lung and splenic functions during sepsis, require further elucidation.
Purpose of the Study:
- To investigate the impact of Tubastatin A (TubA) on lung and splenic pathology in a mouse model of polymicrobial sepsis induced by cecal ligation and puncture (CLP).
- To determine the effects of TubA on immune cell populations within the spleen during sepsis.
- To evaluate the influence of TubA on bacterial clearance and macrophage phagocytic activity in vitro.
Main Methods:
- C57BL/6J mice underwent cecal ligation and puncture (CLP) surgery and were treated with Tubastatin A (TubA) or vehicle control.
- Lung tissues were assessed for pathological changes, and splenic bacterial burden was quantified.
- Splenocytes were analyzed via flow cytometry to profile immune cell populations, and RAW264.7 macrophages were tested for phagocytosis after LPS stimulation with or without TubA.
Main Results:
- TubA treatment significantly attenuated acute lung injury in CLP-induced sepsis.
- TubA administration restored B lymphocyte percentages and increased innate immune cells and macrophages in the spleen.
- Bacterial load in the spleen was reduced by TubA, which also enhanced the phagocytic capacity of murine macrophages in vitro.
Conclusions:
- Tubastatin A demonstrates protective effects against sepsis-induced lung injury and splenic dysfunction.
- TubA modulates immune cell composition and enhances macrophage function, contributing to improved host defense during sepsis.
- These findings provide mechanistic insights into the previously observed survival benefits of TubA in sepsis models, highlighting its therapeutic potential.
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