Abstract
Liver fibrosis is problematic after persistent injury. However, little is known about its response to an acute insult. Accumulation of myeloid lineage cells contributes into the promotion and resolution of inflammation and fibrosis. Using Cre-transgenic mice that specifically mark myeloid lineage cells with EYFP and burn as a model of acute systemic injury, we investigated the role of myeloid lineage cells in the liver after acute injury. Our data show that thermal injury in mice (30% total body surface area) induces fibrosis predominantly around portal venules whereas myeloid cells are enriched throughout the liver. The fibrosis peaks around 1–2 weeks post injury and resolves by week 3. Ablating myeloid cells led to lower fibrosis. Through FACS sorting, we isolated myeloid lineage cells (EYFP +ve cells) from injured animals and from the control uninjured animals and subjected the extracted RNA from these cells to microarray analysis. Microarray analysis revealed an inflammatory signature for EYFP +ve cells isolated from injured animals in comparison with control cells. Moreover, it showed modulation of components of the serotonin (5-HT) pathway in myeloid cells. Antagonizing the 5HT2A/2C receptor decreased fibrosis in thermally injured mice by skewing macrophages away from their pro-fibrotic phenotype. Macrophages conditioned with Ketanserin showed a lower pro-fibrotic phenotype in a co-culture system with mesenchymal cells. There is a spatiotemporal pattern in liver fibrosis post-thermal injury, which is associated with the influx of myeloid cells. Treating mice with a 5HT2A/2C receptor antagonist promotes an anti-fibrotic effect, through modulating the phenotype of macrophages.
Highlights
Severe burn injury results in a systemic response with substantial hepatic alterations[1]
Thermal injury results in liver fibrosis with a unique spatiotemporal pattern Knowing that there is a systemic inflammatory response and profound liver dysfunction post-thermal injury; we investigated whether thermal injury induces a fibrotic response in the liver
We observed a decrease in quiescent hepatic stellate cells, the resident mesenchymal stem cells of the liver, after thermal injury (Fig. 1c, d)
Summary
Severe burn injury results in a systemic response with substantial hepatic alterations[1]. The liver has a diverse role in response to a thermal injury, such as producing acute phase proteins and regulating the systemic inflammatory response[1]. There is a wound-healing response that involves extracellular matrix (ECM) deposition[4]. This is a vital reaction for the liver to protect or repair itself 5. It has been shown that after an acute injury there is fibrosis, which works to shield hepatocytes from toxins rather than having any detrimental role[6]. Clinically fibrosis is an undesirable event and seen as a form of pathology
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