Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis.

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

Tailored nurse-led cardiac rehabilitation after myocardial infarction results in better risk factor control at one year compared to traditional care: a retrospective observational study.

BACKGROUND: Cardiac rehabilitation improves prognosis after an acute myocardial infarction (AMI), however, the optimal method of implementation is unknown. The aim of the study was to evaluate the effect of individually-tailored, nurse-led cardiac rehabilitation on patient outcomes. METHOD: This single-centre retrospective observational study included 217 patients (62 ± 9 years, 73% men). All patients attended cardiac rehabilitation including at least two follow-up consultations with a nurse. Patients receiving traditional care (n = 105) had a routine cardiologist consultation, while for those receiving tailored care (n = 112) their need for a cardiologist consultation was individually evaluated by the nurses. Regression analysis was used to analyse risk factor control and hospital readmissions at one year. RESULTS: Patients in the tailored group achieved better control of total cholesterol (- 0.1 vs + 0.4 mmol/L change between baseline (time of index event) and 12-14-month follow-up, (p = 0.01), LDL cholesterol (- 0.1 vs + 0.2 mmol/L, p = 0.02) and systolic blood pressure (- 2.1 vs + 4.3 mmHg, p = 0.01). Active smokers, at baseline, were more often smoke-free at one-year in the tailored group [OR 0.32 (0.1-1.0), p = 0.05]. There was a no significant difference in re-admissions during the first year of follow-up. In the tailored group 60% of the patients had a cardiologist consultation compared to 98% in the traditional group (p < 0.001). The number of nurse visits was the same in both groups, while the number of telephone contacts was 38% higher in the tailored group (p = 0.02). CONCLUSION: A tailored, nurse-led cardiac rehabilitation programme can improve risk factor management in post-AMI patients.

Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis.

BACKGROUND: Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis. Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. METHODS AND RESULTS: Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE-/- mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. CONCLUSIONS: These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.