Dual Role of Hydrogen Peroxide as an Oxidant in Pneumococcal Pneumonia.

Significance:Streptococcus pneumoniae (Spn), a facultative anaerobic Gram-positive human pathogen with increasing rates of penicillin and macrolide resistance, is a major cause of lower respiratory tract infections worldwide. Pneumococci are a primary agent of severe pneumonia in children younger than 5 years and of community-acquired pneumonia in adults. A major defense mechanism toward Spn is the generation of reactive oxygen species, including hydrogen peroxide (H2O2), during the oxidative burst of neutrophils and macrophages. Paradoxically, Spn produces high endogenous levels of H2O2 as a strategy to promote colonization. Recent Advances: Pneumococci, which express neither catalase nor common regulators of peroxide stress resistance, have developed unique mechanisms to protect themselves from H2O2. Spn generates high levels of H2O2 as a strategy to promote colonization. Production of H2O2 moreover constitutes an important virulence phenotype and its cellular activities overlap and complement those of other virulence factors, such as pneumolysin, in modulating host immune responses and promoting organ injury. Critical Issues: This review examines the dual role of H2O2 in pneumococcal pneumonia, from the viewpoint of both the pathogen (defense mechanisms, lytic activity toward competing pathogens, and virulence) and the resulting host-response (inflammasome activation, endoplasmic reticulum stress, and damage to the alveolar-capillary barrier in the lungs). Future Directions: An understanding of the complexity of H2O2-mediated host-pathogen interactions is necessary to develop novel strategies that target these processes to enhance lung function during severe pneumonia.

Effects of a short-term rehabilitation program on airway inflammation in children with cystic fibrosis.

BACKGROUND: Respiratory therapy in cystic fibrosis (CF) consists of airway clearance, infection control, and reduction of airway inflammation. It is well recognized that physical activity as well as daily chest physiotherapy, enhance airway clearance. We investigated the effects of pulmonary rehabilitation, including physical activity and chest physiotherapy, on airway inflammation in children with CF. METHODS: Eighteen children with stable CF (six females), aged 8.2-16.2 years, participating in a 3-week multidisciplinary inpatient rehabilitation program were recruited. Assessment at the beginning and the end of the program included clinical score, pulmonary function test, exhaled breath condensate (EBC) and sputum analysis. Sputum supernatant and EBC were analyzed for interleukin (IL)-1b, 6, 8, 10, 12, tumor necrosis factor-alpha (TNF-alpha) and LTB4. RESULTS: Median (IQR) symptom scores decreased from 19 [23] to 16 [21], P = 0.005. Vital capacity and FVC increased significantly (P < 0.05). However no difference was found for the total sputum cells and sputum as well as EBC cytokines between the two visits. Significant correlations were found for sputum IL-1 (+), IL-6 (-), and IL-8 (+) to total sputum cell count and neutrophils and for IL-8 to TNF-alpha. CONCLUSIONS: We have shown that a short-term inpatient rehabilitation for children with stable CF with intensive physical activity mainly improve subjective clinical symptoms and measures of lung function such as VC and FVC but does not influence airflow obstruction and airway inflammation as assessed by sputum and EBC analysis.

The lectin-like domain of TNF protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells - a crucial role for protein kinase C-alpha inhibition.

Listeriosis can lead to potentially lethal pulmonary complications in newborns and immune compromised patients, characterized by extensive permeability edema. Listeriolysin (LLO), the main virulence factor of Listeria monocytogenes, induces a dose-dependent hyperpermeability in monolayers of human lung microvascular endothelial cells in vitro. The permeability increasing activity of LLO, which is accompanied by an increased reactive oxygen species (ROS) generation, RhoA activation and myosin light chain (MLC) phosphorylation, can be completely inhibited by the protein kinase C (PKC) alpha/beta inhibitor GO6976, indicating a crucial role for PKC in the induction of barrier dysfunction. The TNF-derived TIP peptide, which mimics the lectin-like domain of the cytokine, blunts LLO-induced hyperpermeability in vitro, upon inhibiting LLO-induced protein kinase C-alpha activation, ROS generation and MLC phosphorylation and upon restoring the RhoA/Rac 1 balance. These results indicate that the lectin-like domain of TNF has a potential therapeutic value in protecting from LLO-induced pulmonary endothelial hyperpermeability.

[Endobronchial ultrasound: practical aspects and clinical applications].

Endobronchial ultrasound (EBUS) has become a major advance in bronchoscopy. Substantial scientific evidence has confirmed its usefulness in lung cancer diagnosis and staging, as well as in other clinical settings. It is of growing importance that endoscopists perform and interpret this imaging method accurately, in order to optimize diagnosis and treatment of their patients. The present article provides a practical and comprehensible review of the two EBUS systems currently available and its main clinical indications.

Microdialysis of the rectus abdominis muscle for early detection of impending abdominal compartment syndrome.

OBJECTIVE: To investigate whether microdialysis is capable of assessing metabolic derangements during intra-abdominal hypertension (IAH), and whether monitoring of the rectus abdominis muscle (RAM) by microdialysis represents a reliable approach in the early detection of organ dysfunctions in abdominal compartment syndrome (ACS). DESIGN: Prospective, randomized, controlled animal study. SETTING: University animal research facility. SUBJECTS: Fifteen isoflurane-anesthetized and mechanically ventilated Sprague-Dawley rats. INTERVENTIONS: IAH of 20 mmHg was induced for 3 h and followed by decompression and reperfusion for another 3-h period (n = 10). Five sham-operated animals served as controls. Microdialysis was performed in the anterior gastric wall, liver, kidney, and RAM. The anterior cervical muscles served as distant reference. Glucose, lactate, pyruvate, and glycerol was analyzed throughout the 6-h experiment. MEASUREMENTS AND MAIN RESULTS: Prolonged IAH induced significant cardiopulmonary dysfunction and persistent abdominal organ injury. Microdialysis revealed a significant increase of lactate/pyruvate and glycerol in kidney, intestine and liver, indicating ischemia, energy failure, and cell membrane damage. In addition, at 3 h IAH glucose was significantly decreased in all organs studied. The distant reference did not show any alteration of lactate/pyruvate, glycerol, and glucose over the entire 6-h observation period. In contrast to the other organs, microdialysis of the RAM showed an early and more pronounced increase of lactate, lactate/pyruvate and glycerol already at 1 h IAH. It is noteworthy that lactate, glycerol, and glucose did not completely recover upon decompression of IAH. CONCLUSIONS: Our data suggest that continuous microdialysis in the RAM may represent a promising tool for early detecting IAH-induced metabolic derangements.

A new model for the study of the abdominal compartment syndrome in rats.

BACKGROUND: The purpose of the present study was to develop of a rodent model of abdominal compartment syndrome (ACS), which allows detailed analysis of intra-abdominal hypertension (IAH)- and decompression-associated reperfusion injury. METHODS: In 20 anesthetized and ventilated Sprague-Dawley rats an IAH of 20 mmHg was induced for 3 h by intraperitoneal infusion of gelatin polysuccinate. After decompression, an additional 3-h period of reperfusion was studied. Sham-operated animals, undergoing identical procedures without IAH induction, served as controls. Controlled hyperventilation and intravenous fluid substitution were adapted to keep PCO(2) <60 mmHg and mean arterial pressure (MAP) >100 mmHg. RESULTS: IAH of 20 mmHg could successfully be maintained for the entire 3-h period. MAP was not affected during IAH, however, decreased upon decompression despite forced fluid resuscitation. CVP was markedly elevated during IAH, but returned to baseline after decompression. Of interest, the IAH-induced reduction of PaO(2) did not recover to baseline after decompression, indicating a persistent deterioration of gas exchange. In contrast, IAH-associated elevation of PaCO(2) normalized during reperfusion. IAH was further accompanied by metabolic acidosis, which persisted after decompression, indicating reperfusion injury. IAH was further associated with a significant increase of serum potassium, lactate, AST, LDH, bilirubin, urea, and creatinine as well as creatine kinase (CK) and CK-MB. Histomorphological analysis revealed parenchymal injury in liver, lung, intestine, and myocardium. CONCLUSION: We established an easily reproducible ACS model in the rat, demonstrating hemodynamic deteriorations and organ dysfunctions similar as known from patients with IAH. Decompression did not restore functional deteriorations, indicating persistent post-ACS reperfusion injury. The model may be suitable to study mechanisms and novel treatment strategies in ACS.