RESUMEN
Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-ß (TGFß) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative 'omics analysis of transcriptomic and proteomic responses to TGFß1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative 'omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFß1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFß1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.
Asunto(s)
Antifibróticos/farmacología , Biología Computacional/métodos , Proteínas de la Matriz Extracelular/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Indoles/farmacología , Piridonas/farmacología , Factor de Crecimiento Transformador beta/fisiología , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Antifibróticos/uso terapéutico , Cadherinas/genética , Cadherinas/metabolismo , Molécula 1 de Adhesión Celular/genética , Molécula 1 de Adhesión Celular/metabolismo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Indoles/uso terapéutico , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Piridonas/uso terapéutico , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Tensinas/genética , Tensinas/metabolismoRESUMEN
PURPOSE@#Periprosthetic fracture (PPF) is a serious complication that occurs in 0.3%-2.5% of all total knee arthroplasties used to treat end-stage arthritis. To our knowledge, there are no studies in the literature that evaluate the association between time to surgery after PPF and early postoperative infections or deep vein thrombosis (DVT). This study tests our hypothesis that delayed time to surgery increases rates of postoperative infection and DVT after PPF surgery.@*METHODS@#Our study cohort included patients undergoing PPF surgery in the American College of Surgeons National Surgical Quality Improvement Program database (2006-2015). The patients were dichotomized based on time to surgery: group 1 with time ≤2 days and group 2 with time >2 days. A 2-by-2 contingency table and Fisher's exact test were used to evaluate the association between complications and time to surgery groups, and multivariate logistic regression was used to adjust for demographics and known risk factors.@*RESULTS@#A total of 263 patients (80% females) with a mean age of 73.9 ± 12.0 years were identified receiving PPF surgery, among which 216 patients were in group 1 and 47 patients in group 2. Complications in group 1 included 3 (1.4%) superficial infections (SI), 1 (0.5%) organ space infection (OSI), 1 (0.5%) wound dehiscence (WD), and 4 (1.9%) deep vein thrombosis (DVT); while complications in group 2 included 1 (2.1%) SI, 1 (2.1%) OSI, 1 (2.1%) DVT, and no WD. No significant difference was detected in postoperative complications between the two groups. However, patients in group 2 were more likely (p = 0.0013) to receive blood transfusions (57.5%) than those in group 1 (32.4%).@*CONCLUSION@#Our study indicates patients with delayed time to surgery have higher chance to receive blood transfusions, but no significant difference in postoperative complications (SI, OSI, WD, or DVT) between the two groups.