Impact of Pioglitazone on Macrophage Dynamics in Adipose Tissues of Cecal Ligation and Puncture-Treated Mice

Matsutani, Takeshi; Tamura, Kazuhiro; Kutsukake, Masahiko; Matsuda, Akihisa; Tachikawa, Eiichi; Uchida, Eiji

doi:10.1248/bpb.b16-00883

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…IL-10 is an anti-inflammatory cytokine that has been implicated in the immunosuppression of sepsis and inability to clear pathogen [22]. Previous studies showed that CLP significantly enhanced IL-10 expression at 12, 24, 48, and 72 h when compared with the sham group [23][24][25]. LPS increased the production of inflammatory cytokine--IL-10 in isolated splenocytes [26] and IL-10 was significantly higher in severe acute pancreatitis on days 7, 9, 11, and 13 [27].…”

Section: Discussionmentioning

confidence: 99%

Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Luo

Wang

et al. 2018

Laboratory Investigation

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Inflammation always accompanies infection during sepsis. Mitochondrial dysfunction and the role of reactive oxygen species (ROS) produced by mitochondria have been proposed in the pathogenesis of sepsis. Maresins have protective and resolving effects in experimental models of infection. In the present study, we investigated the effects of maresin 1 (MaR1) on mitochondrial function in cecal ligation and puncture (CLP)-induced sepsis and sepsis patients to identify mechanisms underlying maresin 1-mediated stimulation of ROS in mitochondria. We found that treatment with MaR1 significantly inhibited production of cytokines, decreased bacterial load in the peritoneal lavage fluid, reduced the number of neutrophils, decreased lactic acid level and upregulated cyclic AMP (cAMP) concentration, with the outcome of decreased lung injury in CLP-induced sepsis in mice. The effects of MaR1 on downregulation nitric oxide (NOX) activity, improvement CAT and SOD activity to inhibit ROS production in mitochondria was dependent on lipoxin receptor (ALX) and cAMP. Survival rates were significantly increased after the treatment of mice with MaR1. In BMDM stimulated with LPS, MaR1 inhibited the ROS production, downregulated enzyme activity, reduced mtO2 production, increased mitochondrial membrane potential, improved adenosine triphosphate (ATP) content and mitochondrial DNA (mtDNA) copy number. Finally, the effects of MaR1 on ROS production in the blood of healthy volunteers stimulated with LPS or sepsis patients were associated with ALX and cAMP. Taken together, these data suggest that treatment with MaR1 could attenuate mitochondrial dysfunction during sepsis through regulating ROS production.

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Section: Discussionmentioning

confidence: 99%

Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Luo

Wang

et al. 2018

Laboratory Investigation

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“…Once PPAR-α and -γ agonism exerts multiple metabolic, inflammatory and immunologic benefits, pioglitazone has been proposed as a candidate against COVID-19 [282,332], despite the lack of current clinical trials to date. Pioglitazone may exert beneficial effects in the RAAS, including marked raise of serum ACE2 levels, which couples with SARS-CoV-2 and preclude viral coupling with attached ACE2 and consequent cell entry, and substantial increase of angiotensin- [1][2][3][4][5][6] and angiotensin-2 receptor (AT2) concentrations [333][334][335][336], undermining angiotensin II actions, may abolish acute lung injury by acting in a range of actions, including positively modulation of macrophage activity, reduction of neutrophil recruitment in response to endotoxin, and reduction of inflammation during sepsis [337][338][339][340][341], and also has direct anti-viral effects [342][343][344][345]. Due to its multiple pleiotropic effects, glitazones could theoretically be candidates for all stages in COVID-19 [332], and is currently being tested in one clinical trial [346].…”

Section: Of Minor Relevancementioning

confidence: 99%

Repurposing existing drugs for COVID-19: an endocrinology perspective

Cadegiani

2020

BMC Endocr Disord

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Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. Main text While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. Conclusion While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.

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“…The CLP-induced mouse model of sepsis mimics the characteristics of clinical sepsis by enteric bacteria. [24][25][26] Therefore, the CLP model is commonly used for the induction of sepsis. When we first induced CLP in mice in the peritoneal cavity, thymic atrophy occurred in all mice, as indicated by a decrease in cell number, and thymocytes, especially double-positive cells, underwent apoptosis in a time-dependent manner (data not shown).…”

Section: Discussionmentioning

confidence: 99%

VISTA Stimulation of VSIG4-Positive Macrophages Strongly Suppresses T Cell Proliferation <i>via</i> Excessive Nitric Oxide Production in Sepsis

Lee

2021

Biological & Pharmaceutical Bulletin

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Organ damage and immune deficiency are important problems in sepsis caused by an excessive immune response. There is controversy about the cause of immune suppression. In this study, we investigated the roles of macrophages that exhibit excessive activity on T cell immunity. Peritoneal macrophages from mice with CLP-induced sepsis migrated to different organs. In particular, VSIG4 positive macrophages appeared in the spleen 48 hr after CLP induction. When cocultured with splenic T cells, VSIG4(+) cells inhibited the proliferation of activated T cells through the release of nitric oxide compared to VSIG4(-) cells. Stimulation of VSIG4(+) cells with VISTA antibody increased the expression of several cytokine genes and the release of nitric oxide, but not phagocytosis, compared to those of hamster IgGstimulated VSIG4(+) cells. When cocultured with splenic T cells, VISTA-stimulated VSIG4(+) cells induced excessive T cell suppression via more NO secretion compared to hamster IgG-stimulated VSIG4(+) cells. Taken together, the current study demonstrates that VSIG4(+) peritoneal macrophages play important roles in inducing immunosuppression and that VISTA acts as a costimulatory receptor in these cells. These data suggest that blocking the migration of VSIG4(+) cells might alleviate excessive immune activity and that blocking VISTA on VSIG4(+) macrophages might play a crucial role in the development of new therapies to prevent T cell suppression in sepsis.

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Impact of Pioglitazone on Macrophage Dynamics in Adipose Tissues of Cecal Ligation and Puncture-Treated Mice

Cited by 6 publications

References 35 publications

Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Repurposing existing drugs for COVID-19: an endocrinology perspective

VISTA Stimulation of VSIG4-Positive Macrophages Strongly Suppresses T Cell Proliferation <i>via</i> Excessive Nitric Oxide Production in Sepsis

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