Role of interleukin-12 and stat-4 in the regulation of airway inflammation and hyperreactivity in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a respiratory pathogen that can cause significant morbidity in infants and young children. Interestingly, the majority of children who acquire a RSV infection do not exhibit severe symptoms. Development of a Th1 response has been associated with resolution of symptoms in viral infections and may explain mild RSV illness. The current study investigated the cytokine response observed in mild disease in C57BL/6 mice that had low airway resistance and mucus production with little pulmonary inflammation. RSV infection in these mice was accompanied by a fourfold increase in interleukin-12(IL-12). Treatment of RSV-infected mice with anti-IL-12 resulted in an increase in airway hyperreactivity, mucus production, and airway inflammation (eosinophilia). Since IL-12 activation is dependent on Stat-4-mediated intracellular signal transduction, similar experiments were performed in Stat-4 deficient mice and demonstrated similar results to those obtained from anti-IL-12 treated mice. Again, there was an increase in airway hyperreactivity and mucus production, and goblet cell hypertrophy. These studies support the importance of IL-12 in the immune response to RSV infection resulting in resolution of disease and protection from inappropriate inflammatory responses.

Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.

IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent.

Airway damage and hyperreactivity induced during respiratory syncytial virus (RSV) infection can have a prolonged effect in infants and young children. These infections can alter the long-term function of the lung and may lead to severe asthma-like responses. In these studies, the role of IL-13 in inducing and maintaining a prolonged airway hyperreactivity response was examined using a mouse model of primary RSV infection. Using this model, there was evidence of significant airway epithelial cell damage and sloughing, along with mucus production. The airway hyperreactivity response was significantly increased by 8 days postinfection, peaked during days 10-12, and began to resolve by day 14. When the local production of Th1- and Th2-associated cytokines was examined, there was a significant increase, primarily in IL-13, as the viral response progressed. Treatment of RSV-infected mice with anti-IL-13 substantially inhibited airway hyperreactivity. Anti-IL-4 treatment had no effect on the RSV-induced responses. Interestingly, when IL-13 was neutralized, an early increase in IL-12 production was observed within the lungs, as was a significantly lower level of viral Ags, suggesting that IL-13 may be regulating an important antiviral pathway. The examination of RSV-induced airway hyperreactivity in STAT6(-/-) mice demonstrated a significant attenuation of the response, similar to the anti-IL-13 treatment. In addition, STAT6(-/-) mice had a significant alteration of mucus-producing cells in the airway. Altogether, these studies suggest that a primary factor leading to chronic RSV-induced airway dysfunction may be the inappropriate production of IL-13.

Role of chemokines in asthmatic airway inflammation.

The incidence of asthma worldwide has increased significantly over the past two decades, especially in young children and in inner cities. Although there are several contributing factors that promote severe asthmatic responses, uncontrolled inflammation leads to the most severe consequences. Chemokines are an interesting target for decreasing the inflammatory response and therefore altering the pathogenesis of asthma reactivity in the lungs. However, it has become clear that there are a number of chemokines that play important roles in various aspects of asthmatic inflammation and reactivity. Identifying the functions each of these chemokines plays during the responses will be imperative to properly target different phases of the asthmatic condition. This review will outline what is known of the role of various chemokines that are produced during asthmatic responses and speculate on the appropriateness of targeting these mediators for therapy.

Excessive ATP degradation during hemodialysis against sodium acetate.

As the initial step in examining the metabolic basis for acetate intolerance, we have tested the hypothesis that excessive adenosine triphosphate (ATP) degradation occurs during hemodialysis against acetate dialysate (compared with the degree of degradation occurring during dialysis against bicarbonate dialysate). Seven patients undergoing long-term dialysis were infused with carbon 14--labeled 8-adenine, and their response to dialysis against acetate was compared with their response to dialysis against bicarbonate. The following changes were observed. During dialysis against acetate, the mean dialysate uric acid--to-creatinine ratio levels were significantly higher than the mean levels observed after dialysis against bicarbonate (p less than 0.001). The mean dialysate uric acid radioactivity--to-creatinine ratio and inosine, hypoxanthine, and xanthine radioactivity--to-creatinine ratio levels were significantly increased during dialysis against acetate (p less than 0.001). There was no significant change in plasma venous hypoxanthine level, but during dialysis against acetate, the arterial hypoxanthine levels (3.7 +/- 1.6 mumol/L) at 60 minutes were significantly higher than the levels observed after dialysis against bicarbonate (1.4 +/- 0.5 mumol/L) (p less than 0.01). These data provide evidence that excessive ATP degradation occurs during hemodialysis against acetate but not during hemodialysis against bicarbonate dialysate.

Isocratic separation of ATP and its degradation products from biological fluids by automated liquid chromatography.

Two groups of metabolites (a) IMP, AMP, ADP, ATP, and cAMP in extracts of fibroblasts and erythrocytes and (b) hypoxanthine, xanthine, adenosine, and inosine in plasma and urine have been separated by ion-pairing reversed-phase chromatography on a microBondapak C18 column, with use of the following reagents: 60 mmol/L KH2PO4, 0.45 mmol/L tetrabutylammonium phosphate, and 1.26 mol/L acetonitrile, pH 3.2 (at 23 degrees C) (group a) and 20 mmol/L KH2PO4, 0.45 mmol/L tetrabutylammonium phosphate, and 0.35 mol/L acetonitrile, pH 2.70 (at 24 degrees C) (group b). Under both sets of conditions, the compounds are completely separated in less than 15 min. The separation is isocratic, so the method is easily adaptable to automation.