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J Surg Res. 2015 Feb;193(2):874-87. doi: 10.1016/j.jss.2014.09.012. Epub 2014 Sep 16.

Cardiac fibroblasts: contributory role in septic cardiac dysfunction.

Author information

1
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
2
Department of Anesthesiology and Pain Relief Center, University of Tokyo Hospital, Tokyo, Japan.
3
Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
4
Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: yhattori@med.u-toyama.ac.jp.

Abstract

BACKGROUND:

Cardiac dysfunction is a frequent and severe complication of septic shock and contributes to the high mortality of sepsis. Although several mechanisms have been suspected to be responsible for sepsis-associated cardiac dysfunction, the precise cause(s) remains unclear to date.

MATERIALS AND METHODS:

We tested the hypothesis that cardiac fibroblasts may play a critical role as a disease modifier involved in sepsis-associated cardiac dysfunction. Human cardiac fibroblasts (HCFs) cultured in vitro were exposed to lipopolysaccharide (LPS). Changes in cardiac morphology and function were assessed in mice with cecal ligation and puncture-induced sepsis.

RESULTS:

In LPS-stimulated HCFs, messenger RNA and protein levels of proinflammatory molecules, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1, were strikingly upregulated. LPS also increased expression and activity of matrix metalloproteinase (MMP)-9, but not MMP-2. LPS-induced expression of α-smooth muscle actin, a classical marker for myoblast differentiation, which was abrogated when MMP-9 small interfering RNA was transfected into HCFs. High gene expression levels of proinflammatory cytokines and MMP-9 were observed in the heart tissues of cecal ligation and puncture-induced septic mice. Histology sections of the hearts from septic mice showed perivascular and interstitial cardiac fibrosis, and echocardiography demonstrated that septic mice had profound cardiac dysfunction. The broad-spectrum MMP inhibitor ONO-4817 significantly alleviated these histologic and functional changes during the acute phase.

CONCLUSIONS:

We suggest that cardiac fibroblasts are of pathogenetic importance in inflammation and fibrosis in the heart during sepsis, leading to cardiac dysfunction that would affect the outcome of sepsis syndrome.

KEYWORDS:

Cardiac dysfunction; Cardiac fibroblast; Cardiac fibrosis; Inflammation; Polymicrobial sepsis

PMID:
25291964
DOI:
10.1016/j.jss.2014.09.012
[Indexed for MEDLINE]

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