Five-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates poly (I:C)-induced airway inflammation in a murine model of asthma.

BACKGROUND: Asthma can frequently be induced or exacerbated by respiratory viral infections. Oxidative stress might also play an essential role in the pathogenesis of allergic airway diseases, indicating that antioxidant therapy may have a potential effect in controlling allergic airway diseases. Recent studies showed that 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) has the potential ability to modulate NADPH oxidase activity, indicating the antioxidant activity of AICAR. This study investigated the inhibitory effects of AICAR as an anti-inflammatory modulator on allergic airway inflammation in murine animal models. METHODS: The anti-inflammatory effects of AICAR were evaluated in two experimental asthma models: (1) an ovalbumin (OVA)-induced experimental asthma model and (2) an OVA plus polyinosinic-polycytidylic acid [poly (I:C)]-induced experimental asthma model to mimic respiratory viral infections. The inhibitory effects of AICAR in poly (I:C)-mediated signalling for NF-kappaB activation and production of TNF-alpha were analysed in vitro. RESULTS: AICAR was shown to have a marginal inhibitory effect in an OVA-induced asthma model. Interestingly, AICAR significantly attenuated poly (I:C)-induced airway hyperresponsiveness and airway inflammation, as shown by the attenuation of the influx of total inflammatory cells and soluble products into bronchoalveolar lavage fluid, such as macrophages, eosinophils, IL-5, IL-13, TNF-alpha and IFN-gamma. AICAR also significantly reduced the serum levels of OVA-specific IgE and IgG2a antibodies. Histologic and flow cytometric studies showed that AICAR inhibited poly (I:C)-induced lung inflammation and the infiltration of CD11b+CD11c+ dendritic cells into the lung. Moreover, AICAR effectively inhibited poly (I:C)-mediated activation of NF-kappaB and the production of TNF-alpha. CONCLUSION: These findings suggest that AICAR may be a novel immunomodulator with promising beneficial effects for the treatment of respiratory viral infection in airway allergic diseases.

4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model.

BACKGROUND: 4-1 BB, a member of the tumour necrosis factor receptor superfamily, functions as a co-stimulatory molecule. Recently, stimulation of the 4-1 BB pathway was shown to suppress antigen-specific CD4(+) T cell and subsequent T cell-dependent humoral immune responses. OBJECTIVE: We examined the effect of agonistic anti-4-1 BB monoclonal antibody (mAb) treatment on allergic asthma, in which allergen-specific type 2 helper T cells (Th2) have been shown to play an important role. METHODS: BALB/c mice were systemically sensitized with intraperitoneal injections of ovalbumin (OVA) and alum on days 0 and 14, and then challenged with inhaled OVA on days 28, 29 and 30. In test groups, the agonistic anti-4-1 BB mAb was administered at the time of initial systemic sensitization with OVA. On day 31, mice were challenged with inhaled methacholine, and enhanced pause was measured as an index of airway hyper-responsiveness (AHR). Levels of OVA-specific IgE in serum, and levels of various cytokines in bronchoalveolar lavage (BAL) fluids were measured. The severity of airway inflammation was determined by differential cell counts in BAL fluids and histopathologic lung analysis. To evaluate local immunity, we cultured lymphocytes from draining perihilar lymph nodes and evaluated the proliferative response to OVA and the levels of IL-5 in the culture supernatant. In addition, the functional mechanism of 4-1 BB stimulation was evaluated in splenocytes obtained at day 7 after systemic OVA sensitization. RESULTS: We found that treatment with the anti-4-1 BB mAb significantly decreased AHR and the production of allergen-specific IgE. Bronchial inflammation, however, had only partially improved and the levels of IL-4 and IL-5 in BAL fluids showed only a small degree of reduction compared with the control Ig-treated mice. Thoracic lymphocytes from anti-4-1 BB-treated mice showed significant suppression of OVA-induced proliferation and IL-5 production. In anti-4-1 BB-treated mice, splenocytes exhibited poor proliferation and marked apoptosis 7 days after systemic OVA challenge. CONCLUSION: These results suggest that stimulation of the 4-1 BB pathway effectively suppresses some features of allergic asthma, including allergen-specific IgE production and AHR, through deletion of allergen-specific Th2 cells. However, we found that bronchial allergic inflammation was not strictly mediated by suppression of the Th2 immune response in this murine model of asthma. Despite these somewhat contradictory effects, intervention in the 4-1 BB pathway might provide a potential novel immunotherapeutic approach for treatment of allergic asthma.

Chlamydia pneumoniae infection enhances cellular proliferation and reduces steroid responsiveness of human peripheral blood mononuclear cells via a tumor necrosis factor-alpha-dependent pathway.

BACKGROUND: Although epidemiological studies have found an association between Chlamydia pneumoniae infection and severe asthma, the causality and underlying mechanism are largely unknown. We hypothesized that C. pneumoniae infection increases the proliferation and enhances the survival of immune and inflammatory cells, resulting in reduced responsiveness to corticosteroids and suggesting that the underlying mechanism is related to a TNF-alpha-dependent pathway. METHODS: Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro in the presence or absence of C. pneumoniae infection. Responsiveness to corticosteroids was assayed by adding dexamethasone, and the underlying mechanism was investigated by treating cells with infliximab that is a chimeric anti-TNF-alpha monoclonal antibody. Cellular proliferation and apoptosis was assessed by thymidine uptake and counting apoptotic cells using flow cytometry. RESULTS: Cellular proliferation was significantly higher in C. pneumoniae-infected PBMCs than in uninfected PBMCs, which is more prominent in Th2-dominant microenvironment. The anti-proliferative and pro-apoptotic effect of corticosteroid were significantly reduced in C. pneumoniae-infected PBMCs compared with uninfected PBMCs. The proliferative effect of C. pneumoniae infection and the reduced response to corticosteroid were effectively reversed by blocking the TNF-alpha pathway at least partially. CONCLUSION: C. pneumoniae infection enhanced the proliferation and survival of immune and inflammatory cells, resulting in steroid resistance. The reversal of these phenomena by the TNF-alpha inhibitor suggests that TNF-alpha may play an important role in the induction of steroid dependence or resistance. A TNF-alpha inhibitor may therefore be a candidate agent for managing steroid-dependent or -resistant severe asthma.

Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population.

PURPOSE: Since 1991 we have performed more than 300 anatomical radical perineal prostatectomies at Brooke Army and Wilford Hall Medical Centers, and were initially aware of 8 patients who presented with unsolicited postoperative fecal incontinence. We determined the incidence of fecal and urinary incontinence following radical prostatectomy, defined parameters to identify patients at risk for fecal complaints following radical prostatectomy, and estimated the impact of fecal incontinence on lifestyle and activities. MATERIALS AND METHODS: Initially a validated 26-question telephone survey was used to evaluate 227 patients who had previously undergone radical prostatectomy at 1 of our 2 institutions. Based on results of the telephone survey a national survey was mailed to 1,200 radical prostatectomy patients randomly selected from a nationwide database of Department of Defense health care system beneficiaries. All patients had undergone radical perineal or retropubic prostatectomy at least 12 months before being contacted for the survey. RESULTS: Responses to the telephone survey from 227 patients revealed that fecal incontinence was a problem after radical retropubic (5%) and perineal (18%) prostatectomy and less than 50% of those with fecal incontinence had told the physician. Our mail survey (response rate 80% and 78% usable for analysis, 784 radical perineal and 123 perineal) strongly indicated that fecal incontinence after radical prostatectomy is a problem nationwide. Frequency of fecal incontinence (daily, weekly, monthly or less than monthly occurrences) was significantly higher among radical perineal (3, 9, 3 and 16%) compared to retropubic prostatectomy (2, 5, 3, and 8%) patients (p=0.002). Fecal incontinence had a significant negative effect on patient social or entertainment activities (p=0.029), and travel and vacation plans (p=0.043). Radical perineal compared to retropubic prostatectomy patients were more likely to wear a pad for stool leakage (p=0.013), experienced more accidents (p=0.001), had larger amounts of stool leakage (p=0.002) and had less formed stools (p=0.001). Of radical perineal prostatectomy patients only 14% and of retropubic only 7% with fecal incontinence had ever told a health care provider about it, even when the incontinence was severe. Responses to our survey concerning urinary incontinence showed that radical perineal prostatectomy patients had a lower rate of urinary incontinence immediately after prostatectomy compared to retropubic (79 versus 85%, p=0.043). A higher proportion of perineal patients reported that all urinary leakage had ceased, that is full continence had returned (perineal 70%, retropubic 53%, p=0.001). A smaller proportion of perineal patients found it necessary to wear a pad to protect from urinary incontinence (perineal 39%, retropubic 56%, p=0.004). CONCLUSIONS: Fecal incontinence following radical prostatectomy occurs more frequently than previously recognized. In general fecal incontinence among radical perineal and retropubic prostatectomy patients surpasses the expected incidence rate of 4% for this age group (60 to 70 years) but incidence is significantly higher for radical perineal prostatectomy patients. However, radical perineal prostatectomy patients have a significantly lower incidence of urinary incontinence than those treated with retropubic prostatectomy. Surgeons who perform radical retropubic and perineal prostatectomy should be aware of the possibility of fecal and/or urinary incontinence and associated symptoms.