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.