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The mitogen-activated protein (MAP) kinases are involved in cellular responses to many stimuli, including hypoxia. MAP kinase signaling is regulated by a family of phosphatases that include MAP kinase phosphatase-I (MKP-1). We hypothesized that mice lacking the Mkp-1 gene would have exaggerated chronic hypoxia-induced pulmonary hypertension. Wild-type (WT) and [Mkp-1.sup.-/-] mice were exposed to either 4 wk of normoxia or hypobaric hypoxia. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as demonstrated by the ratio of the right ventricle to the left ventricle plus septum weights [RV(LV + S)], and greater vascular remodeling. However, the right ventricular systolic pressures, the RV/(LV + S), and the medial wall thickness of 100- to 300-[micro]m vessels was significantly greater in the [Mkp-1.sup.-/-] mice than in the WT mice following 4 wk of hypobaric hypoxia. Chronic hypoxic exposure caused no detectable change in eNOS protein levels in the lungs in either genotype: however, [Mkp-1.sup.-/-] mice had lower levels of eNOS protein and lower lung NO production than did WT mice. No iNOS protein was detected in the lungs by Western blotting in any condition in either genotype. Both arginase I and arginase II protein levels were greater in the lungs of hypoxic [Mkp-1.sup.-/-] mice than those in hypoxic WT mice. Lung levels of proliferating cell nuclear antigen were greater in hypoxic [Mkp-1.sup.-/-] than in hypoxic WT mice. These data are consistent with the concept that MKP-1 acts to restrain hypoxia-induced arginase expression and thereby reduces vascular remodeling and the severity of pulmonary hypertension. nitric oxide synthase; arginase; pulmonary vascular remodeling doi: 10.1152/ajpheart.00813.2009.

Mitogen-activated protein kinase phosphatase-1 (MKP-1) is essential in limiting the proinflammatory response to lipopolysaccharide (LPS). We hypothesized that Mkp-[1.sup.-/-] mice would respond to low-dose LPS with a fall in blood pressure due to augmented expression of inducible nitric oxide (NO) synthase (iNOS). To test this hypothesis, Mkp-[1.sup.-/-] mice and their wild-type littermates were treated with 10 [micro]g/kg iv LPS, and mean arterial blood pressure (MAP) and exhaled NO production (exNO) were measured. Tissues were harvested for an assessment of iNOS protein levels. Wild-type mice had no change in MAP or exNO during the experimental period, whereas Mkp-[1.sup.-/-] mice had a fall (P < 0.005) in MAP [79 [+ or -] 5% of baseline (BL)] and an increase (P < 0.01) in exNO (266 [+ or -] 50% of BL) after 150 min. The tissue levels of iNOS were greater in Mkp-[1.sup.-/-] than in wild-type mice. In additional experiments, 60 rain after LPS treatment, Mkp-[1.sup.-/-] and wild-type mice were given [N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, and MAP and exNO were monitored for 90 min. Treatment with L-NAME prevented the LPS-induced increase in exNO and decrease in MAP but resulted in decreased exNO and elevated MAP in wild-type mice. Aminoguanidine prevented the increase in exNO and the fall in MAP caused by LPS in Mkp-[1.sup.-/-] mice, without significantly affecting MAP or exNO in wild-type mice. These results demonstrate that a deficiency of MKP-1 results in an exaggerated hypotensive response to LPS mediated by augmented iNOS expression. We speculate that defects in the Mkp-1 gene may increase susceptibility for the development of septic shock. lipopolysaccharide; septic shock; cell signaling; nitric oxide

Background: Biliary strictures present a unique diagnostic challenge to clinicians as they can be caused by both benign and malignant conditions. With the high mortalities associated with hepatopancreaticobiliary malignancies, accurate and rapid tissue diagnosis is imperative and typically done before initiation of treatment. However, the exact sensitivity of standard cytology from endoscopic retrograde cholangiopancreatography (ERCP) to diagnose malignancy remains unclear because of wide distribution of reported values in the literature. Furthermore, the use of radical surgery to obtain tissue when cytology is indeterminate has led to questions about the role of ERCP in patients with biliary strictures. Methods: A PubMed search was conducted using the terms ERCP, cytology, and brushings. Articles reviewed were published between 2002 and 2012, had patient population with biliary stricture, and had ERCP brushing results and final pathology available for review. The cytology and pathology data were abstracted from each study, and the combined overall sensitivity was calculated. Results: Sixteen studies were identified, with sensitivities ranging from 6%–64% and 99% confidence intervals (CIs) ranging from ±6% to ±32%. A combined total of 1556 patients were included, with positive ERCP cytology results in 358 cases. On final pathology, however, 861 patients were positive for malignancy. When the data were combined, we found an overall sensitivity of 41.6% ± 3.2% (99% CI) with a negative predictive value of 58.0% ± 3.2% (99% CI). Conclusions: ERCP brushings suffer from low sensitivity and negative predictive value. This study questions the utility of ERCP to change the surgical management of these diseases in patients with radiographic evidence of a neoplasm or high suspicion of a malignancy. [ABSTRACT FROM AUTHOR]

Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from L-arginine (L-Arg). However, little is known of the effect of L-Arg on vascular compliance (Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous L-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R0). Hypoxia resulted in the expected increase in arterial resistance (Ra) as well as a decrease in both Ca and Ca. L-Arg had little effect on Ra, Ca, or Cv in isolated lungs from normoxic animals. L-Arg decreased Ra in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R0, and L-Arg reversed this increase in R0. L-Arg increased exhaled NO, and inhibition of L-Arg uptake attenuated the L-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in Ca was reversed by L-Arg, suggesting that L-Arg may improve CH-induced right ventricular dysfunction. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein (MAP) kinases are involved in cellular responses to many stimuli, including hypoxia. MAP kinase signaling is regulated by a family of phosphatases that include MAP kinase phosphatase-1 (MKP-1). We hypothesized that mice lacking the Mkp-1 gene would have exaggerated chronic hypoxia-induced pulmonary hypertension. Wild-type (WT) and Mkp-1-/- mice were exposed to either 4 wk of normoxia or hypobaric hypoxia. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as demonstrated by the ratio of the right ventricle to the left ventricle plus septum weights [RV(LV + S)], and greater vascular remodeling. However, the right ventricular systolic pressures, the RV/(LV + S), and the medial wall thickness of 100- to 300-μm vessels was significantly greater in the Mkp-1-/- mice than in the WT mice following 4 wk of hypobaric hypoxia. Chronic hypoxic exposure caused no detectable change in eNOS protein levels in the lungs in either genotype; however, Mkp-1-/- mice had lower levels of eNOS protein and lower lung NO production than did WT mice. No iNOS protein was detected in the lungs by Western blotting in any condition in either genotype. Both arginase I and arginase 11 protein levels were greater in the lungs of hypoxic Mkp-1-/- mice than those in hypoxic WT mice. Lung levels of proliferating cell nuclear antigen were greater in hypoxic Mkp-1-/- than in hypoxic WT mice. These data are consistent with the concept that MKP-1 acts to restrain hypoxia-induced arginase expression and thereby reduces vascular remodeling and the severity of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (C(a)) in right ventricular work, a decrease in C(a) would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from L-arginine (L-Arg). However, little is known of the effect of L-Arg on vascular compliance (C(v)) in the lung. We hypothesized that exposure to CH would decrease C(a) and that this effect would be reversed by exogenous L-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R(0)). Hypoxia resulted in the expected increase in arterial resistance (R(a)) as well as a decrease in both C(a) and C(v). L-Arg had little effect on R(a), C(a), or C(v) in isolated lungs from normoxic animals. L-Arg decreased R(a) in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R(0), and L-Arg reversed this increase in R(0). L-Arg increased exhaled NO, and inhibition of L-Arg uptake attenuated the L-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in C(a) was reversed by L-Arg, suggesting that L-Arg may improve CH-induced right ventricular dysfunction.