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The unclear mechanism that ischemia–reperfusion injury (IRI) contributes to the development of primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) remains a major issue in lung transplantation. Differentially expressed PGD-related genes and CLAD-related genes during IRI (IRI-PGD common genes and IRI-CLAD common genes) were identified using GEO datasets (GSE127003, GSE8021, GSE9102) and GeneCards datasets. Enrichment analysis and four network analyses, namely, protein-protein interaction, microRNA (miRNA)-gene, transcription factor (TF)-gene, and drug-gene networks, were then performed. Moreover, GSE161520 was analyzed to identify the differentially expressed core miRNAs during IRI in rats. Finally, Pearson correlation analysis and ROC analysis were performed. Eight IRI-PGD common genes (IL6, TNF, IL1A, IL1B, CSF3, CXCL8, SERPINE1, and PADI4) and 10 IRI-CLAD common genes (IL1A, ICAM1, CCL20, CCL2, IL1B, TNF, PADI4, CXCL8, GZMB, and IL6) were identified. Enrichment analysis showed that both IRI-PGD and IRI-CLAD common genes were significantly enriched in “AGE-RAGE signaling pathway in diabetic complication” and “IL-17 signaling pathway”. Among the core miRNAs, miR-1-3p and miR-335 were differentially expressed in IRI rats. Among core TFs, CEBPB expression had a significant negative correlation with P/F ratio (r = −0.33, P = 0.021). In the reperfused lung allografts, the strongest positive correlation was exhibited between PADI4 expression and neutrophil proportion (r = 0.76, P < 0.001), and the strongest negative correlation was between PADI4 expression and M2 macrophage proportion (r = −0.74, P < 0.001). In lung allografts of PGD recipients, IL6 expression correlated with activated dendritic cells proportion (r = 0.86, P < 0.01), and IL1B expression correlated with the neutrophils proportion(r = 0.84, P < 0.01). In whole blood of CLAD recipients, GZMB expression correlated with activated CD4+ memory T cells proportion (r = 0.76, P < 0.001).Our study provides the novel insights into the molecular mechanisms by which IRI contributes to PGD and CLAD and potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Smad7 is an intracellular inhibitory protein that antagonizes the signaling of TGF-β family members. Deletion of Smad7 in the mouse leads to an abnormality in heart development. However, whether Smad7 has a functional role in the development of other organs has been elusive. Here we present evidence that Smad7 imparts a role to eye development in the mouse. Smad7 is expressed in both the lens and retina in the developing embryonic eye. Depletion of Smad7 caused various degrees of coloboma and microphthalmia with alterations in cell apoptosis and proliferation in eyes. Smad7 was implicated in lens differentiation but was not required for the induction of the lens placode. The development of the periocular mesenchyme was retarded with the down-regulation of Bmp7 and Pitx2 in mutant mice. Retinal spatial patterning was affected by Smad7 deletion and was accompanied by altered bone morphogenetic protein (BMP) signaling. At late gestation stages, TGF-β signaling was up-regulated in the differentiating retina. Smad7 mutant mice displayed an expanded optic disc with increasing of sonic hedgehog (SHH) signaling. Furthermore, loss of Smad7 led to a temporal change in retinal neurogenesis. In conclusion, our study suggests that Smad7 is essential for eye development. In addition, our data indicate that alterations in the signaling of BMP, TGF-β and SHH likely underlie the defects in eye development caused by Smad7 deletion. [ABSTRACT FROM AUTHOR]

The molecular basis of the lymphatic development remains largely unknown. Using zebrafish as a model, we discovered a novel role for the Ras guanine-releasing protein 1 (RasGRP1), a protein involved in Ras activation in lymphangiogenesis. Secondary lymphatic sprouts from the posterior cardinal vein give rise to thoracic duct which is the first lymphatic vessel in zebrafish. Knockdown of rasgrp1 by injecting morpholino in zebrafish embryos impaired formation of thoracic duct accompanied by pericardial and truck edema, whereas blood vessel development of the embryos was largely unaffected. In rasgrp1-knockdown embryos, the number of sprouts producing the string of parachordal lymphangioblast cells was reduced. Meanwhile the total number of the secondary sprouts was not changed. As a result, the number of venous intersegmental vessels was increased, whereas the number of lymphatic vessel was reduced at a later stage. The lymphatic developmental defects caused by rasgrp1 knockdown could be rescued by ectopic expression of a constitutively active HRas. Further analysis revealed that RasGRP1 knockdown could synergize with flt4/vegfr3 knockdown to induce defects in lymphangiogenesis. Taken together, this finding demonstrates a critical role for RasGRP1 in lymphatic development in zebrafish. [ABSTRACT FROM AUTHOR]