Patients with ED but no clinical cardiovascular disease have a peripheral vascular defect in endothelium-dependent and -independent vasodilation that occurs before the development of other overt functional or structural systemic vascular disease and is independent of other traditional cardiovascular risk factors.

Interleukin-23 (IL-23The resurgence of Mycobacterium tuberculosis infection linked to the human immunodeficiency virus epidemic highlights the importance of cellular immunity in controlling the growth of this pathogen. Effective host defense against pulmonary infection with M. tuberculosis requires the coordinated actions of both the innate and adaptive immune systems (10). Interleukin-12 (IL-12) is well-established as a cytokine released by antigen-presenting cells early in M. tuberculosis infection, and this cytokine is critical for the generation of a Th1 polarized adaptive immune response and subsequent host defenses. Indeed, the exogenous administration of IL-12 augments M. tuberculosis clearance (6,11,25). IL-23 has recently been identified as a member of the IL-12 cytokine family and may also play a role in host defense against this pathogen. IL-23 is a heterodimer that shares an identical p40 subunit with IL-12 but contains a unique p19 chain that closely resembles IL-12 p35 (26). Secreted by dendritic cells and other antigenpresenting cells, IL-23 stimulates the production of gamma interferon (IFN-␥) by activated/memory CD45RO ϩ T cells but not naïve CD45RA ϩ cells. In contrast, IL-12 elicits IFN-␥ from both subsets. IL-23 also induces the proliferation of activated/ memory T cells but not naïve T cells. IL-12 and IL-23 share binding affinity for the IL-12R␤1 subunit; however, IL-23 binds to a distinct IL-23 receptor (IL-23R), whereas IL-12 utilizes IL-12R␤2 as its coreceptor (27).The comparative roles of IL-12 and IL-23 in host defense against a variety of infections are actively under investigation. Through Toll-like receptor 4 signaling, IL-23, but not IL-12, has been shown to play a critical role in stimulating T-cell release of IL-17 following infection with Klebsiella pneumoniae (15), while specific roles for IL-23 in immune defense against the intracellular bacteria Salmonella enteritidis and Francisella tularensis have also been found (9, 21). In regard to M. tuberculosis infections, recent studies have demonstrated a greater sensitivity in IL-12/23 p40 Ϫ/Ϫ mice than in IL-12 p35 Ϫ/Ϫ animals (5, 17). Moreover, macrophages rapidly express IL-23 when exposed to mycobacterial antigens, suggesting an immune-stimulatory role for this cytokine during infection (4, 33).The evidence of a role for IL-23 in the development of immunity against several intracellular pathogens, together with increasing interest in the use of biologic response modifiers to treat disease, led us to study the effects of localized, transient expression of IL-23 during early pulmonary M. tuberculosis infection. In this report, we show that local IL-23 gene delivery using a replication-defective adenovirus vector (AdIL-23) resulted in markedly decreased mycobacterial burden in the lungs up to 28 days after infection. AdIL-23 treatment significantly decreased lung inflammation in infected animals despite increasing numbers of activated CD4 ϩ T cells in lungs and draining lymph nodes. Cultures of T cells from draining

Keratinocyte growth factor (KGF) prevents alpha-naphthylthiourea (ANTU)-induced permeability edema ex vivo. To explore the mechanisms in this involved effect, we administered KGF (5 mg/kg, intratracheally) 48 h prior to ANTU (50 mg/kg, intraperitoneally). Several groups were studied: phosphate-buffered saline/dimethylsulfoxide (PBS/DMSO) (vehicles), PBS/ANTU, and KGF/ANTU. At 90 min after ANTU injection the lungs were removed, ventilated, and perfused ex vivo for 180 min. Quantification of fluorescein isothiocyanate (FITC)-labeled dextran in bronchoalveolar lavage fluid (BALF) was used to assess alveolar capillary barrier permeability. KGF attenuated ANTU-induced edema and blockade of sodium transport, with ouabain (10(-3) M) or amiloride (10(-4) M) added ex vivo reversed this effect. FITC-dextran was increased in the PBS/ANTU group as compared with the PBS/DMSO group, indicating permeability edema. In the KGF/ANTU group, there was concentration of BALF FITC-dextran, consistent with permeability edema and increased alveolar fluid export. Albumin space measurements showed similar increases in permeability in the PBS/ANTU and KGF/ANTU groups. Extravascular lung water (measured with radiolabeled erythrocytes) was decreased in the KGF/ANTU group. Following KGF pretreatment, uninjured lungs exported more intratracheal PBS than normal lungs following terbutaline stimulation ex vivo. In conclusion, KGF, through type II alveolar pneumocyte hyperplasia with increased sodium-potassium-adenosine triphosphatase (Na,K-ATPase) activity, attenuated ANTU-induced edema formation by potentiating alveolar fluid clearance.

The presence of arginase could, in part, explain the decreased expression of CD3zeta . These findings provide a novel mechanism that may explain the T cell dysfunction observed in patients with PTB.

We have previously reported that keratinocyte growth factor (KGF) attenuates alpha-naphthylthiourea-induced lung injury by upregulating alveolar fluid transport. The objective of this study was to determine the effect of KGF pretreatment in Pseudomonas aeruginosa pneumonia. A 5% bovine albumin solution with 1 microCi of (125)I-labeled human albumin was instilled into the air spaces 4 or 24 h after intratracheal instillation of P. aeruginosa, and the concentration of unlabeled and labeled proteins in the distal air spaces over 1 h was used as an index of net alveolar fluid clearance. Alveolocapillary barrier permeability was evaluated with an intravascular injection of 1 microCi of (131)I-albumin. In early pneumonia, KGF increased lung liquid clearance (LLC) compared with that in nonpretreated animals. In late pneumonia, LLC was significantly reduced in the absence of KGF but increased above the control value with KGF. KGF pretreatment increased the number of polymorphonuclear cells recovered in the bronchoalveolar lavage fluid and decreased bacterial pulmonary translocation. In conclusion, KGF restores normal alveolar epithelial fluid transport during the acute phase of P. aeruginosa pneumonia and LLC in early and late pneumonia. Host response is also improved as shown by the increase in the alveolar cellular response and the decrease in pulmonary translocation of bacteria.

Tumor necrosis factor (TNF), a compartmentalized cytokine, is a key mediator in the systemic inflammatory response syndrome and may play a role in multiorgan failure. To assess whether compartmentalization of alveolar TNF is preserved following lung injury, isolated perfused lungs from Sprague-Dawley rats were given intratracheally 1 ml/kg of phosphate-buffered saline (PBS), 0.1 mg/kg of lipopolysaccharide (LPS), or 125,000 units of murine recombinant TNF (mrTNF). To induce lung leak, one group of rats was given 50 mg/kg of alpha-naphthylthiourea (ANTU) intraperitoneally. Then, 125,000 units mrTNF was given intratracheally to these lungs. Samples of perfusate were assayed for TNF by the L929 cytotoxicity assay before (0 min) and 180 min after the intratracheal challenge, and bronchoalveolar lavage (BAL) was performed for TNF assay. ANTU increased lung leak but intratracheal TNF and LPS did not. The isolated perfused lung preparation expressed small amounts of perfusate TNF and underwent minimal leak that was not caused by TNF release. Endogenous or exogenous intrapulmonary TNF remained predominantly compartmentalized, but following ANTU, TNF readily appeared in the perfusate. Compartmentalization of alveolar TNF is lost during alveolar-capillary injury, suggesting that the injured lung may contribute to a systemic inflammatory response and subsequent multiorgan failure.

Tumor necrosis factor (TNF) plays a pivotal role in inflammatory phenomena that culminate in either pathogenesis or resistance in mycobacterial disease. The regulatory role of TNF in murine tuberculosis was examined by administering a recombinant adenovirus encoding a fusion protein consisting of the human 55-kDa TNF receptor extracellular domain and the mouse IgG heavy chain domain (AdTNFR). During acute infections with Mycobacterium tuberculosis, AdTNFR pretreatment induced elevated mycobacterial burdens of 1 log10 in the tissues of H37Ra-infected mice and 2 log10 (spleen and liver) and 4 log10 (lungs) in H37Rv-infected mice. In mice infected chronically with H37Rv, AdTNFR treatment induced a 3-log10 increase of M. tuberculosis in the lungs, in which a tuberculous bronchopneumonia developed with numerous acid-fast bacilli visible in alveoli and bronchi. Administration of AdTNFR may serve as a useful model for studying the pathogenesis and chemotherapy of progressive primary tuberculosis.

Alcohol consumption has been described as a risk factor for infection with Mycobacterium tuberculosis, but its contribution to tuberculosis has been difficult to isolate from other adverse socioeconomic factors. Our objective was to evaluate the impact of alcohol consumption on pulmonary infection with M. tuberculosis in a murine model. BALB/c mice were maintained on the Lieber-DeCarli liquid ethanol diet or a liquid control diet and infected intratracheally with low-dose M. tuberculosis H37Rv. Lung organism burdens, lung and lung-associated lymph node CD4 ؉ -and CD8 ؉ -lymphocyte numbers and rates of proliferation, and CD4 ؉ -lymphocyte cytokine production levels were compared between the groups. The alcohol-consuming mice had significantly higher lung organism burdens than the control mice, and the CD4 ؉ -and CD8 ؉ -lymphocyte responses to pulmonary infection with M. tuberculosis were blunted in the alcohol group. Lymphocyte proliferation and production of gamma interferon were decreased in the CD4؉ lymphocytes from the alcohol-consuming mice. Additionally, lung granulomas were significantly smaller in the alcohol-consuming mice. In conclusion, murine alcohol consumption is associated with decreased control of pulmonary infection with M. tuberculosis, which is accompanied by alterations in the region-specific CD4؉ -and CD8 ؉ -lymphocyte responses and defective lung granuloma formation.For many years, the medical literature worldwide has suggested an association between alcohol consumption and active tuberculosis in humans (7,10,16,19,23,24,28,44). Screening alcohol-abusing subjects in an urban setting for tuberculous infection revealed rates of active tuberculosis that were 28-fold greater than those of age-matched residents and rates of positive tuberculin tests that were 1.5-fold greater than those of agematched residents of the same locale (19). In another setting, heavy alcohol consumption conferred a twofold-heightened risk for developing active tuberculosis (10). Additionally, a person with active tuberculosis who routinely frequented a neighborhood bar was found to have infected 41 persons who were frequent clients of the bar, one-third of whom developed active tuberculosis (24). Similar reports of increased prevalence of tuberculosis in alcohol-consuming subjects exist outside of the United States. In London, England, regular alcohol use increased the risk of contracting tuberculosis more than twofold (28), and alcohol abuse was found to be a risk factor in the acquisition of multidrug-resistant tuberculosis in Russia (44).However, the bulk of the evidence of an association between alcohol consumption and tuberculosis is circumstantial, and not all studies consistently demonstrate this association (34, 42). Among homeless persons in San Francisco, despite very high rates of tuberculosis, alcohol abuse was not found to be a significant risk factor (34). Regular consumers of alcohol frequently have confounding lifestyle factors, such as other substance (i.e., illicit drugs or tobacco) abuse, low socioeco...