BACKGROUND & AIMS: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice following induction of acute pancreatitis. METHODS: We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1flox/flox mice). Acute pancreatitis was induced in these mice (HMGB1flox/flox mice served as controls) following injection of L-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS: Following injection of L-arginine or cerulein, Pdx1-Cre; HMGB1flox/flox mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1flox/flox mice following L-arginine- or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA Nfκb, degradation of Iκb, and phosphorylation of Mapk. Inhibitors of reactive oxygen species (N-acetyl-L-cysteine) blocked L-arginine–induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of Nfκb in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1flox/flox and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival following L-arginine injection. CONCLUSIONS: In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.

Phospholipase A2 (sPLA2), pivotal for allergic and inflammatory response, hydrolyses phosphatidylcholine (PC) to lysophosphatidylcholine (LPC). In present study, the role of LPC in allergic airway disease manifestation was studied using mouse model. Balb/c mice were immunized using cockroach extract (CE) and LPC release was blocked by sPLA2 inhibitor. Airway hyperresponse (AHR), lung-histology, total and differential leukocyte count (TLC&DLC), Th2 type cytokines, sPLA2 activity and LPC levels in bronchoalveolar lavage fluid (BALF) were measured. Exogenous LPC was given to the mice with or without CE sensitization, to demonstrate its role in allergic airway disease manifestation. Anti-CD1d antibody was given to study the involvement of natural killer T (NKT) cells in LPC induced response. AHR, lung-inflammation, TLC, DLC, Th2 type cytokines, sPLA2 activity and LPC levels were increased on CE challenge. sPLA2 activity and LPC release was blocked by sPLA2-inhibitor, which decreased AHR, and inflammatory parameters. Exogenous LPC with or without CE sensitization increased above parameters. CE challenge or LPC exposure increased LY49C+TCRβ+ NKT cells in BALF and spleen, which was reduced by anti-CD1d antibody, accompanied with reduction in AHR and allergic airway inflammation parameters. Conclusively, LPC induces allergic airway disease manifestation and it does so probably via CD1d-restricted LY49C+TCRβ+ NKT cells.

Objective:To determine gender differences and secular trends in total, low-density lipoprotein (LDL) and high DL (HDL) cholesterol and triglycerides using a large hospital database in India.Methods:All blood lipid tests evaluated from July 2007 to December 2014 were analyzed. Details of gender and age were available. Statin therapy was obtained at two separate periods. Trends were calculated using linear regression and Mantel-Haenszel X2.Results:Data of 67395 subjects (men 49,904, women 17,491) aged 51 ± 12 years were analyzed. Mean levels (mg/dl) were total cholesterol 174.7 ± 45, LDL cholesterol 110.7 ± 38, non-HDL cholesterol 132.1 ± 44.8, HDL cholesterol 44.1 ± 10, triglycerides 140.8 ± 99, and total: HDL cholesterol 4.44 ± 1.5. Various dyslipidemias in men/women were total cholesterol ≥200 mg/dl 25.4/36.4%, LDL cholesterol ≥130 mg/dl 28.1/35.0% and ≥100 mg/dl 54.4/66.4%, non-HDL cholesterol ≥160 mg/dl 25.5/29.6%, HDL cholesterol <40/50 mg/dl 54.4/64.4%, and triglycerides ≥150 mg/dl 34.0/26.8%. Cholesterol lipoproteins declined over 7 years with greater decline in men versus women for cholesterol (Blinearregression = −0.82 vs. −0.33, LDL cholesterol (−1.01 vs. −0.65), non-HDL cholesterol (−0.88 vs. −0.52), and total: HDL cholesterol (−0.02 vs. −0.01). In men versus women there was greater decline in prevalence of hypercholesterolemia (X2trend 74.5 vs. 1.60), LDL cholesterol ≥130 mg/dl (X2trend 415.5 vs. 25.0) and ≥100 mg/dl (X2trend 501.5 vs. 237.4), non-HDL cholesterol (X2trend 77.4 vs. 6.85), total: HDL cholesterol (X2trend 212.7 vs. 10.5) and high triglycerides (X2trend 10.8 vs. 6.15) (P < 0.01). Use of statins was in 2.6% (36/1405) in 2008 and 9.0% (228/2527) in 2014 (P < 0.01). Statin use was significantly lower in women (5.8%) than men (10.3%).Conclusions:In a large hospital - database we observed greater hypercholesterolemia and low HDL cholesterol in women. Mean levels and prevalence of high total, LDL, non-HDL and total: HDL cholesterol declined over 7 years. A lower decline was observed in women. This was associated with lower use of statins.

No abstract