Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

Abstract

BackgroundLiver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches.MethodsEight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses.ResultsWe observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-α and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group.ConclusionsWe constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.

Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice†

“…CBDL mice develop intrapulmonary shunting and become hypoxemic on a background of cholestatic liver disease, which fulfills the three diagnostic criteria of HPS . To our knowledge, only one study has reported on CBDL in mice as a potential model for HPS, which, however, failed to demonstrate intrapulmonary shunts due to methodological issues . Our findings are in line with knowledge from human patients and prior work in rats, in which it was shown that shunts start to develop early after CBDL induction and do not require advanced fibrosis.…”

Requirement of miR‐9‐dependent regulation of Myocd in PASMCs phenotypic modulation and proliferation induced by hepatopulmonary syndrome rat serum

“…For all experiments, PASMCs treated with normal rat serum or HPS rat serum come from the same split cells. The purity and identity of PASMCs was verified by their typical morphological pattern (peak and valley formation) and immunocytochemical staining with an antibody against SM-a-actin, as previously reported [23,24]. When the cells reached approximately 80% confluence, the original serum was replaced with 0.1% FBS.…”

Ex vivo perfusion induces a time- and perfusate-dependent molecular repair response in explanted porcine lungs

“…PubMed was searched for all messenger RNA (mRNA) microarray studies describing significantly upregulated gene expression in nonfetal lung cells or tissue in the setting of ALI, acute respiratory distress syndrome, pulmonary ischemia‐reperfusion, and/or primary pulmonary graft dysfunction. A total of 31 gene lists including 843 unique genes were identified from 23 articles . Based on the experimental models used in each study, these gene lists were subdivided into one of 3 “mechanical/noninfectious” categories (ischemia‐reperfusion, stretch, primary graft dysfunction) or one of 3 “toxic/infectious” categories (infection, sepsis, toxicity).…”

“…Genome‐wide microarray studies have previously demonstrated that ALI induces coordinated changes in the expression of hundreds of genes . We hypothesized that analyzing a representative subset of these previously described ALI‐related transcripts would allow for more precise, objective, and mechanistic evaluation of lung tissue injury and repair before, during, and after EVLP.…”