Heme oxygenase inhibition enhances neutrophil migration into the bronchoalveolar spaces and improves the outcome of murine pneumonia-induced sepsis.

A reduction of the neutrophil migration into the site of infection during cecal ligation and puncture-induced sepsis increases host mortality. Inhibition of heme oxygenase (HO) prevents this neutrophil paralysis and improves host survival in the cecal ligation and puncture model. Taking into account that almost 50% of all sepsis cases are a consequence of pneumonia, we designed the present study to determine the role of HO in an experimental model of pneumonia-induced sepsis. The objective of this study was to evaluate whether the inhibition of HO improves the outcome and pathophysiologic changes of sepsis induced by an intratracheal instillation of Klebsiella pneumoniae. The pretreatment of mice subjected to pneumonia-induced sepsis with ZnDPBG (zinc deuteroporphyrin 2,4-bis glycol), a nonspecific HO inhibitor, increased the number of neutrophils in the bronchoalveolar spaces, reduced the bacterial load at the site of infection, and prevented the upregulation of CD11b and the downregulation of CXCR2 on blood neutrophils. Moreover, the pretreatment with ZnDPBG decreased alveolar collapse, attenuating the deleterious changes in pulmonary mechanics and gas exchanges and, as a consequence, improved the survival rate of mice from 0% to ∼20%. These results show that heme oxygenase is involved in the pathophysiology of pneumonia-induced sepsis and suggest that HO inhibitors could be helpful for the management of this disease.

Effects of inducible nitric oxide synthase inhibition in bronchial vascular remodeling-induced by chronic allergic pulmonary inflammation.

Vascular remodeling is an important feature in asthma pathophysiology. Although investigations suggested that nitric oxide (NO) is involved in lung remodeling, little evidence established the role of inducible NO synthase (iNOS) isoform in bronchial vascular remodeling. The authors investigated if iNOS contribute to bronchial vascular remodeling induced by chronic allergic pulmonary inflammation. Guinea pigs were submitted to ovalbumin exposures with increasing doses (1∼5 mg/mL) for 4 weeks. Animals received 1400W (iNOS-specific inhibitor) treatment for 4 days beginning at 7th inhalation. Seventy-two hours after the 7th inhalation, animals were anesthetized, mechanical ventilated, exhaled NO was collected, and lungs were removed and submitted to picrosirius and resorcin-fuchsin stains and to immunohistochemistry for matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-ß (TGF-ß). Collagen and elastic fiber deposition as well as MMP-9, TIMP-1, and TGF-ß expression were increase in bronchial vascular wall in ovalbumin-exposed animals. The iNOS inhibition reduced all parameters studied. In this model, iNOS inhibition reduced the bronchial vascular extracellular remodeling, particularly controlling the collagen and elastic fibers deposition in pulmonary vessels. This effect can be associated to a reduction on TGF-ß and on metalloproteinase-9/TIMP-1 vascular expression. It reveals new therapeutic strategies and some possible mechanism related to specific iNOS inhibition to control vascular remodeling.

Eosinophilic inflammation and airway hyper-responsiveness are profoundly inhibited by a helminth (Ascaris suum) extract in a murine model of asthma.

BACKGROUND: The increase of atopic disorders in developed countries has been associated with the decline of infectious diseases, including helminthic infections. We have already demonstrated that adult worm extracts from Ascaris suum (ASC) suppress the IgE antibody production against unrelated antigens. OBJECTIVE: Here we investigated the influence of ASC on the development of pulmonary eosinophilic inflammation in a murine model of asthma. METHODS: Heat-coagulated egg white alone (EWI) or mixed with ASC (EWI + ASC) was implanted subcutaneously in B10.A or C57BL/6 mice, and 14 days later they were challenged intratracheally with OVA or exposed to aerosolized OVA for 4 days. RESULTS: The suppressive effect of ASC was demonstrated on the accumulation of cells into airways, with reduction of eosinophil numbers and of eosinophil peroxidase activity in EWI + ASC-immunized mice. This effect correlated with a marked reduction of IL-5 and IL-4 levels in the BAL from C57BL/6 and B10. A mice, respectively, and of eotaxin in BAL and lung tissue from both strains. OVA-specific IgG1 and IgE levels were also impaired in serum and BAL from these mice. Airway hyper-reactivity to methacholine was obtained in B10. A mice sensitized with EWI, but the respiratory mechanical parameters returned to normal levels in EWI + ASC-immunized mice. CONCLUSION: These results indicate that ASC has a profound inhibitory effect on lung inflammation and hyper-responsiveness and that suppression of IL-5 or IL-4 and of eotaxin contributes to this effect.

[Creatine kinase BB activity in the serum and bronchial aspirate of preterm newborns with respiratory distress syndrome]. / Actividad de la isoenzima CKBB en suero y broncoaspirado de recién nacidos pretérmino con síndrome de distrés respiratorio.

OBJECTIVE: The aim of this study was to test the utility of serum creatine kinase (CK) isoenzyme determinations as a marker of tissue injury in preterm newborns with respiratory distress syndrome (RDS). PATIENTS AND METHODS: Two groups of neonates were studied, 26 suffering from RDS who required mechanical ventilation and 20 healthy newborns with gestational ages, hours of life and birth weights similar to the first group. The activity of CK and its isoenzymes was determined in the bronchial aspirate and serum samples that were obtained before and 24 hours after exogenous surfactant therapy. The isoenzymes were separated by electrophoresis on agarose gel and their activity expressed as a percentage of the total CK. Total proteins were quantified in the bronchial aspirate and CK enzymatic activity expressed in U/mg of protein x 10-3. RESULTS: The CK-BB isoenzyme was significantly increased (p < 0.001) in the serum of infants with RDS compared with the control group. In the bronchial aspirate, the isoenzymatic study showed that the CK-BB isoenzyme represented 98-100% of the total enzymatic CK activity. CONCLUSIONS: The study shows significant differences in the CK isoenzyme patterns of neonates with RDS compared to controls. An increase in serum levels of the CK-BB isoenzyme could be an effective marker of tissue injury in lung disease in the newborn.

Aspiration in seriously ill patients: a study of amylase in bronchial secretions

Bronchial secretions from 21 patients with moderate to severe chest infections were obtained by transtracheal aspiration. Six seriously ill patients showed greatly increased levels of amylase activity in the bronchial secretions compared with those found in the 15 less ill patients. This amylase was almost certainly derived from oropharyngeal contents and its presence suggests that aspiration may be more common in comatose and semi-comatose patients than is generally appreciated. (Summary)