Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.

RATIONALE: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.

Angiotensin II favors progression to heart failure in diabetic hearts: role of myocardial fatty acid oxidation downregulation

Purpose: Diabetic myocardium is particularly vulnerable to develop heart failure in response to chronic stress conditions including hypertension or myocardial infarction. We have recently observed that angiotensin II (Ang II)-mediated downregulation of the fatty acid oxidation pathway favors occurrence of heart failure by myocardial accumulation of lipids (lipotoxicity). Because diabetic heart is exposed to high levels of circulating fatty acid, we determined whether insulin resistance favors development of heart failure in mice with Ang II-mediated myocardial remodeling.Methods: To study the combined effect of diabetes and Ang II-induced heart remodeling, we generated leptin-deficient/insulin resistant (Lepob/ob) mice with cardiac targeted overexpression of angiotensinogen (TGAOGN). Left ventricular (LV) failure was indicated by pulmonary congestion (lung weight/tibial length>+2SD of wild-type mice). Myocardial metabolism and function were assessed during in vitro isolated working heart perfusion.Results: Forty-eight percent of TGAOGN mice without insulin resistance exhibited pulmonary congestion at the age of 6 months associated with increased myocardial BNP expression (+375% compared with WT) and reduced LV power (developed pressure x cardiac output; -15%). The proportion of mice presenting heart failure was markedly increased to 71% in TGAOGN mice with insulin resistance (TGAOGN/Lepob/ob). TGAOGN/Lepob/ob mice with heart failure exhibited further increase of BNP compared with failing non-diabetic TGAOGN mice (+146%) and further reduction of cardiac power (-59%). Mice with insulin resistance alone (Lepob/ob) did not exhibit signs of heart failure or LV dysfunction. Myocardial fatty acid oxidation measured during in vitro perfusion was markedly increased in non-failing hearts from Lepob/ob mice (+380% compared with WT) and glucose oxidation decreased (-72%). In contrast, fatty acid and glucose oxidation did not differ from Lepob/ob mice in hearts from TGAOGN/Lepob/ob mice without heart failure. However, both fatty acid and glucose oxidation were markedly decreased (-47% and -48%, respectively, compared with WT/Lepob/+) in failing hearts from TGAOGN/Lepob/ob mice. Reduction of fatty acid oxidation was associated with marked reduction of protein expression of a number of regulatory enzymes implied in fatty acid oxidation.Conclusions: Insulin resistance favors the progression to heart failure during chronic exposure of the myocardium to Ang II. Our results are compatible with a role of Ang II-mediated downregulation of fatty acid oxidation, potentially promoting lipotoxicity.

The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study.

Experimental evidence indicates a role of the N-methyl-D-aspartate receptor in the pathogenesis of brain injury occurring during cardiac surgery with cardiopulmonary bypass (CPB). Dextromethorphan is a noncompetitive antagonist of this receptor with a favorable safety profile. Thirteen children age 3-36 months undergoing cardiac surgery with expected CPB of 60 minutes or more were randomly assigned to treatment with dextromethorphan (36-38 mg/kg/day) or placebo administered by naso-gastric tube. Dextromethorphan was absorbed well and reached putative therapeutic levels in blood and cerebrospinal fluid. Adverse effects were not observed. Mild hemiparesis developed after operation in one child of each group, and severe encephalopathy in one of the placebo group. Sharp waves were recorded in postoperative continuous electroencephalography in all placebo (n = 7) but only in 2/6 dextromethorphan treated children (p = 0.02). Pre- and postoperative cranial magnetic resonance imaging (MRI) revealed less pronounced ventricular enlargement in the dextromethorphan group (not significant). An increase of periventricular white matter lesions was visible in two placebo-treated children only. No elevations of cerebrospinal fluid enzymes were observed in either group. Although children with dextromethorphan showed less abnormalities in electroencephalography and MRI, dissimilarities of the treatment groups by chance diminished conclusions to possible protective effects of dextromethorphan at this time.

Accuracy of Brain Multimodal Monitoring to Detect Cerebral Hypoperfusion After Traumatic Brain Injury.

OBJECTIVE:: To examine the accuracy of brain multimodal monitoring-consisting of intracranial pressure, brain tissue PO2, and cerebral microdialysis-in detecting cerebral hypoperfusion in patients with severe traumatic brain injury. DESIGN:: Prospective single-center study. PATIENTS:: Patients with severe traumatic brain injury. SETTING:: Medico-surgical ICU, university hospital. INTERVENTION:: Intracranial pressure, brain tissue PO2, and cerebral microdialysis monitoring (right frontal lobe, apparently normal tissue) combined with cerebral blood flow measurements using perfusion CT. MEASUREMENTS AND MAIN RESULTS:: Cerebral blood flow was measured using perfusion CT in tissue area around intracranial monitoring (regional cerebral blood flow) and in bilateral supra-ventricular brain areas (global cerebral blood flow) and was matched to cerebral physiologic variables. The accuracy of intracranial monitoring to predict cerebral hypoperfusion (defined as an oligemic regional cerebral blood flow < 35 mL/100 g/min) was examined using area under the receiver-operating characteristic curves. Thirty perfusion CT scans (median, 27 hr [interquartile range, 20-45] after traumatic brain injury) were performed on 27 patients (age, 39 yr [24-54 yr]; Glasgow Coma Scale, 7 [6-8]; 24/27 [89%] with diffuse injury). Regional cerebral blood flow correlated significantly with global cerebral blood flow (Pearson r = 0.70, p < 0.01). Compared with normal regional cerebral blood flow (n = 16), low regional cerebral blood flow (n = 14) measurements had a higher proportion of samples with intracranial pressure more than 20 mm Hg (13% vs 30%), brain tissue PO2 less than 20 mm Hg (9% vs 20%), cerebral microdialysis glucose less than 1 mmol/L (22% vs 57%), and lactate/pyruvate ratio more than 40 (4% vs 14%; all p < 0.05). Compared with intracranial pressure monitoring alone (area under the receiver-operating characteristic curve, 0.74 [95% CI, 0.61-0.87]), monitoring intracranial pressure + brain tissue PO2 (area under the receiver-operating characteristic curve, 0.84 [0.74-0.93]) or intracranial pressure + brain tissue PO2+ cerebral microdialysis (area under the receiver-operating characteristic curve, 0.88 [0.79-0.96]) was significantly more accurate in predicting low regional cerebral blood flow (both p < 0.05). CONCLUSION:: Brain multimodal monitoring-including intracranial pressure, brain tissue PO2, and cerebral microdialysis-is more accurate than intracranial pressure monitoring alone in detecting cerebral hypoperfusion at the bedside in patients with severe traumatic brain injury and predominantly diffuse injury.

Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.

BACKGROUND/AIMS: After treatment with heat-killed Propionibacterium acnes mice show dense hepatic granuloma formation. Such mice develop liver injury in an interleukin (IL)-18-dependent manner after challenge with a sublethal dose LPS. As previously shown, LPS-stimulated Kupffer cells secrete IL-18 depending on caspase-1 and Toll-like receptor (TLR)-4 but independently of its signal adaptor myeloid differentiation factor 88 (MyD88), suggesting importance of another signal adaptor TIR domain-containing adapter inducing IFN-beta (TRIF). Nalp3 inflammasome reportedly controls caspase-1 activation. Here we investigated the roles of MyD88 and TRIF in P. acnes-induced hepatic granuloma formation and LPS-induced caspase-1 activation for IL-18 release. METHODS: Mice were sequentially treated with P. acnes and LPS, and their serum IL-18 levels and liver injuries were determined by ELISA and ALT/AST measurement, respectively. Active caspase-1 in LPS-stimulated Kupffer cells was determined by Western blotting. RESULTS: Macrophage-ablated mice lacked P. acnes-induced hepatic granuloma formation and LPS-induced serum IL-18 elevation and liver injury. Myd88(-/-) Kupffer cells, but not Trif(-/-) cells, exhibited normal caspase-1 activation upon TLR4 engagement in vitro. Myd88(-/-) mice failed to develop hepatic granulomas after P. acnes treatment and liver injury induced by LPS challenge. In contrast, Trif(-/-) mice normally formed the hepatic granulomas, but could not release IL-18 or develop the liver injury. Nalp3(-/-) mice showed the same phenotypes of Trif(-/-) mice. CONCLUSIONS: Propionibacterium acnes treatment MyD88-dependently induced hepatic granuloma formation. Subsequent LPS TRIF-dependently activated caspase-1 via Nalp3 inflammasome and induced IL-18 release, eventually leading to the liver injury.

Influence of socioeconomic factors on delays, management and boutcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

Background¦The outcome after primary percutaneous coronary intervention (pPCI) for STElevation¦Myocardial Infarction (STEMI) is strongly affected by time delays. In thepresent study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients from a well-defined region of the French part of Switzerland.¦Method¦A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analyzed for the following socioeconomic factors: level of education, gender, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment by fibrinolysis or patients immediately referred for CABG.¦Therefore, 352 patients were finally included.¦Results¦At one year, there was no difference in mortality amongst the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly higher for patients with a low level of education, Swiss citizens and non-married patients with median differences of 40 minutes, 48 minutes, and 60 minutes, respectively (p<0.05).¦Nevertheless, no difference was found regarding in-hospital management and clinical outcome.¦Conclusion¦This study demonstrates that symptom-to-first-medical-contact time is higher amongst people with a lower educational level, Swiss-citizens, and non-married people. Because of the low mortality rate in general, these differences in time delays did not affect clinical outcomes. Still, primary prevention measures should particularly focus on these vulnerable populations.

Peroxynitrite is a key mediator of the cardioprotection afforded by ischemic postconditioning in vivo.

Myocardial ischemic postconditioning (PosC) describes an acquired resistance to lethal ischemia-reperfusion (I/R) injury afforded by brief episodes of I/R applied immediately after the ischemic insult. Cardioprotection is conveyed by parallel signaling pathways converging to prevent mitochondria permeability transition. Recent observations indicated that PostC is associated with free radicals generation, including nitric oxide (NO(.)) and superoxide (O2 (.-)), and that cardioprotection is abrogated by antioxidants. Since NO. And O2 (. -) react to form peroxynitrite, we hypothesized that postC might trigger the formation of peroxyntrite to promote cardioprotection in vivo. Rats were exposed to 45 min of myocardial ischemia followed by 3h reperfusion. PostC (3 cycles of 30 seconds ischemia/30 seconds reperfusion) was applied at the end of index ischemia. In a subgroup of rats, the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (FeTPPS) was given intravenously (10 mg/kg(-1)) 5 minutes before PostC. Myocardial nitrotyrosine was determined as an index of peroxynitrite formation. Infarct size (colorimetric technique and plasma creatine kinase-CK-levels) and left ventricle (LV) function (micro-tip pressure transducer), were determined. A significant generation of 3-nitrotyrosine was detected just after the PostC manoeuvre. PostC resulted in a marked reduction of infarct size, CK release and LV systolic dysfunction. Treatment with FeTPPS before PostC abrogated the beneficial effects of PostC on myocardial infarct size and LV function. Thus, peroxynitrite formed in the myocardium during PostC induces cardioprotective mechanisms improving both structural and functional integrity of the left ventricle exposed to ischemia and reperfusion in vivo.

Protective effects of hypercapnic acidosis on ventilator-induced lung injury.

To investigate whether respiratory acidosis modulates ventilator-induced lung injury (VILI), we perfused (constant flow) 21 isolated sets of normal rabbit lungs, ventilated them for 20 min (pressure controlled ventilation [PCV] = 15 cm H(2)O) (Baseline) with an inspired CO(2) fraction adjusted for the partial pressure of CO(2) in the perfusate (PCO(2) approximately equal to 40 mm Hg), and then randomized them into three groups. Group A (control: n = 7) was ventilated with PCV = 15 cm H(2)O for three consecutive 20-min periods (T1, T2, T3). In Group B (high PCV/normocapnia; n = 7), PCV was given at 20 (T1), 25 (T2), and 30 (T3) cm H(2)O. The targeted PCO(2) was 40 mm Hg in Groups A and B. Group C (high PCV/hypercapnia; n = 7) was ventilated in the same way as Group B, but the targeted PCO(2) was approximately equal to 70 to 100 mm Hg. The changes (from Baseline to T3) in weight gain (Delta WG: g) and in the ultrafiltration coefficient (Delta K(f) = gr/min/ cm H(2)O/100g) and the protein and hemoglobin concentrations in bronchoalveolar lavage fluid (BALF) were used to assess injury. Group B experienced a significantly greater Delta WG (14.85 +/- 5.49 [mean +/- SEM] g) and Delta K(f) (1.40 +/- 0.49 g/min/cm H(2)O/100 g) than did either Group A (Delta WG = 0.70 +/- 0.43; Delta K(f) = 0.01 +/- 0.03) or Group C (Delta WG = 5.27 +/- 2.03 g; Delta K(f) = 0.25 +/- 0.12 g/min/cm H(2)O/ 100 g). BALF protein and hemoglobin concentrations (g/L) were higher in Group B (11.98 +/- 3.78 g/L and 1.82 +/- 0.40 g/L, respectively) than in Group A (2.92 +/- 0.75 g/L and 0.38 +/- 0.15 g/L) or Group C (5.71 +/- 1.88 g/L and 1.19 +/- 0.32 g/L). We conclude that respiratory acidosis decreases the severity of VILI in this model.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Severe traumatic brain injury in Switzerland - feasibility and first results of a cohort study.

BACKGROUND: We aimed to study the incidence and outcome of severe traumatic brain injury (TBI) in Switzerland and to test the feasibility of a large cohort study with case identification in the first 24 hours and 6-month follow-up. METHODS: From January to June 2005, we consecutively enrolled and followed up all persons with severe TBI (Abbreviated Injury Score of the head region >3 and Glasgow Coma Scale <9) in the catchment areas of 3 Swiss medical centres with neurosurgical facilities. The primary outcome was the Extended Glasgow Outcome Scale (GOSE) after 6 months. Secondary outcomes included survival, Functional Independence Mea - sure (FIM), and health-related quality of life (SF-12) at defined time-points up to 6 months after injury. RESULTS: We recruited 101 participants from a source population of about 2.47 million (ie, about 33% of Swiss population). The incidence of severe TBI was 8.2 per 100,000 person-years. The overall case fatality was 70%: 41 of 101 persons (41%) died at the scene of the accident. 23 of 60 hospitalised participants (38%) died within 48 hours, and 31 (53%) within 6 months. In all hospitalised patients, the median GOSE was 1 (range 1-8) after 6 months, and was 6 (2-8) in 6-month survivors. The median total FIM score was 125 (range 18-126); median-SF-12 component mea - sures were 44 (25-55) for the physical scale and 52 (32-65) for the mental scale. CONCLUSIONS: Severe TBI was associated with high case fatality and considerable morbidity in survivors. We demonstrated the feasibility of a multicentre cohort study in Switzerland with the aim of identifying modifiable determinants of outcome and improving current trauma care.