Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion

Abstract

Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from ischemia reperfusion after lung transplantation, but the impact of ischemia reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from 6 subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. KEGG pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were down-regulated in the post-reperfusion time compared with baseline. Long pentraxin-3 (PTX3), a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5 fold increase, p=0.04). Fibronectin leucine rich transmembrane protein (FLRT3), a gene associated with cell adhesion and receptor signaling, was the most down-regulated gene (4.3 fold decrease, p=0.04). Ischemia reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of non-obese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant.

Protein biomarkers associated with primary graft dysfunction following lung transplantation

“…The interplay of recipient anthropomorphic characteristics with the activity of protein biomarkers and this effect on the risk of PGD deserves more study. For example, recent work has shown the impact of ischemia-reperfusion injury on gene expression profiles specifically in adipose tissue (21). This study further supports the association of several protein biomarkers with levels of adiposity, in addition to cytokines specifically associated with hypoxic adipose tissue as discussed above.…”

“…However, we must acknowledge the possibility that additional pathways of injury exist that are yet to be discovered, using biomarkers yet to be studied. Further research for biomarker discovery using metabolomics, proteomics, microarray, and gene expression technology, as has already been done by some (3,21,31,37,50,52), may detect novel biomarkers associated with PGD and yield a more comprehensive understanding of the pathways of injury.…”

PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation

“…To confirm the relevance of these findings, we investigated the effects of PLK1 inhibition on myofibroblasts by pathway enrichment on the downregulated genes. This revealed various enriched categories, including complement and coagulation cascades [ 18 , 19 ], platelet activation [ 20 , 21 ], p53 signaling, lysosomes, AGE-RAGE signaling, VEGF signaling, phagosomes, and PI3K-Akt signaling ( Figure 5D ). Furthermore, we applied GSEA to the DEGs, which revealed that inhibiting PLK1 reduces myofibroblast differentiation in the late inflammatory phase in part via the MAPK pathway ( Figure 5E ).…”

Genome-wide expression of the residual lung reacting to experimental Pneumonectomy

“…Amer1 is a widespread expressed gene during mouse embryonic development which acts as a negative modulator of WNT/β-catenin pathway serving pleiotropic functions during organogenesis [ 74 ]. Flrt3 is expressed in a wide variety of tissues and is involved in cell adhesion and adipocytokine signaling pathways [ 75 ], while, notably, being reported as the most downregulated gene in thoracic visceral adipose tissue after lung allograft reperfusion [ 76 ]. Efnb2 is an angiogenesis factor regulating both pulmonary branch and vascular development through the control of VEGF-induced angiogenesis and lymphangiogenesis [ 77 ].…”