The biological factors that promote inflammation or nonalcoholic steatohepatitis (NASH) in the setting of nonalcoholic fatty liver disease remain incompletely understood. Clinical studies have demonstrated an association between obstructive sleep apnea (OSA) and both inflammation and fibrosis in NASH, but the mechanism has not been identified. In this study, we use in vitro modeling to examine the impact of intermittent hypoxia on the liver. Hepatocyte, stellate cell, and macrophage cell lines were exposed to intermittent or sustained hypoxia. Candidate genes associated with inflammation, fibrosis, and lipogenesis were analyzed. Circulating cytokines were assessed in human serum of patients with nonalcoholic fatty liver disease. Intermittent hypoxia results in significant induction of interleukin (IL)‐6 expression in both hepatocytes and macrophages. The increase in IL‐6 expression was independent of hypoxia inducible factor 1 induction but appeared to be in part related to antioxidant response element and nuclear factor kappa B activation. Mature microRNA 365 (miR‐365) has been demonstrated to regulate IL‐6 expression, and we found that miR‐365 expression was decreased in the setting of intermittent hypoxia. Furthermore, macrophage cell lines showed polarization to an M1 but not M2 phenotype. Finally, we found a trend toward higher circulating levels of IL‐6 in patients with OSA and NASH. Conclusion: Intermittent hypoxia acts as a potent proinflammatory stimulus, resulting in IL‐6 induction and M1 macrophage polarization. Increased IL‐6 expression may be due to both induction of antioxidant response element and nuclear factor kappa B as well as inhibition of miR‐365 expression. Higher levels of IL‐6 were observed in human samples of patients with OSA and NASH. These findings provide biological insight into mechanisms by which obstructive sleep apnea potentiates inflammation and fibrosis in patients with fatty liver disease. (Hepatology Communications 2017;1:326–337)

Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet‐induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786‐797)

Background: High Flow Nasal Cannula (HFNC) has gained widespread use for acute hypoxemic respiratory failure on the basis of recent publications demonstrating fewer intubations and perhaps lower mortality in certain situations. However, a subset of patients initiated on HFNC for respiratory failure ultimately do require intubation. Our goal is to identify patient level features predictive of this outcome. Materials and methods: This is a retrospective cohort study of patients with hypoxemic respiratory failure treated with HFNC. Individuals were described as having "succeeded" (if weaned from HFNC) or "failed" (if they required intubation). A variety of easily measurable variables were evaluated for their ability to predict intubation risk, analyzed via a multivariate logistic regression model. Results: Of a total of 74 subjects, 42 "succeeded" and 32 "failed." Net fluid balance in the first 24 hours after HFNC initiation was significantly lower in the success group (-33 ± 80 vs. +72 ± 117 mL / h, p <0.01). An adjusted model finds only fluid balance and the previously described Respiratory Rate-Oxygenation (ROX) index (a ratio of the oxygen saturation (SpO 2) divided by the fraction of inspired oxygen (FiO 2) to the respiratory rate (RR), [SpO 2 /FiO 2 ]/RR) at 12 hours as significant predictors of successful weaning (negative fluid balance adjusted OR 0.77 [0.62-0.96] for-10 mL/Hr increments, p = 0.02; ROX adjusted OR 1.72 p <0.01). Conclusions: Negative fluid balance while on HFNC discriminates well between those who will require intubation versus those who will be successfully weaned.