Increased susceptibility to ischemia causes exacerbated response to laser microinjuries in the cirrhotic liver
Background & Aims: Fractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested in other tissues. As a first step towards determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response. Methods: Healthy and cirrhotic rats were treated with a fractional laser then euthanized from 0hr up to 14d after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion. Results: Healthy rats showed little damage beyond the initial microinjury and healed completely by 7d without scarring.  In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6hr after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4hr. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death. Conclusions: The cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications would need to be made to account for this to continue developing a microinjury treatment for cirrhosis. Regardless, the remarkable results of microinjury treatment in skin warrant further investigation for fibrotic conditions throughout the body. Overall design: Differential gene expression anaysis with a difference-in-differences model comparing laser-treated healthy and laser-treated cirrhotic liver samples. Paired control samples from an untreated section of the liver is used to control for differences between the untreated healthy and cirrhotic livers