Angiotensin II type 1 receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium deficiency

BACKGROUND: Chronic potassium (K+) deficiency, one of the well-known causes of renal tubulointerstitial injury, is associated with an alteration in vasoactive mediators including persistent generation of renal cortical angiotensin (Ang) II despite the suppression of plasma Ang II, and suppression of urinary nitrite/nitrate excretion. We tested the hypothesis that K+-deficiency-induced renal tubulointerstitial injury could be mediated by Ang II or a reduction in nitric oxide. METHODS: Rats were fed a K+-deficient diet (0.01% K+) alone, or with either losartan or l-arginine (L-Arg) in drinking water. Control rats were fed with a normal K+ diet (0.36% K+). At the end of 10 weeks, kidneys were excised and renal injury was evaluated. RESULTS: Serum K+ was similarly depressed in all three groups receiving the K+-deficient diet. Rats on the K+-deficient diet alone developed renal hypertrophy and tubulointerstitial fibrosis with an increase in tubular osteopontin expression, macrophage infiltration and type III collagen deposition. Administration of losartan significantly reduced renal hypertrophy and prevented tubulointerstitial injury in the cortex, although some medullary injury occurred. In contrast, administration of L-Arg did not attenuate tubulointerstitial injury in the cortex, despite a complete recovery of urinary nitrate excretion. Mild but significant improvement of tubular osteopontin expression and macrophage infiltration were observed in the medulla of L-Arg-treated hypokalemic rats. CONCLUSIONS: These results indicate that hypokalemic renal injury is mediated, at least in part, by Ang II via the Ang II type 1 receptor, with a lesser contribution mediated by a reduction in nitric oxide. Losartan may be beneficial in preventing hypokalemic tubulointerstitial injury.     

Regional lung functional impairment in acute airway obstruction and pulmonary embolic dog models assessed with gadolinium-based aerosol ventilation and perfusion magnetic resonance imaging

RATIONALE AND OBJECTIVES: Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-based aerosol ventilation and perfusion magnetic resonance (MR) images were used to define regional functional impairment in acute airway obstruction (AO) and pulmonary embolic (PE) dog models. METHODS: The aerosol study was performed in 10 anesthetized normal dogs in a supine position during 20-minute spontaneous inhalation of an aerosol of 100- or 200-mmol-Gd/L Gd-DTPA solute produced by an ultrasonic nebulizer in an open-circuit delivery system, combined with a dynamic perfusion study after a 3-second intravenous bolus injection of a 0.1 mmol/kg dose of Gd-DTPA. These MR studies were also performed in the same 10 dogs approximately 30 minutes after obstructing the segmental (n = 6) or lobar (n = 4) bronchus with a balloon catheter, and in another six dogs after segmental (n = 6) and lobar (n = 4) pulmonary arterial embolization with enbucrilate. Regional lung enhancement was assessed on time-signal intensity (SI)-curves and ventilation- and perfusion-weighted images produced by a subtraction technique. RESULTS: The normal lungs were gradually and gravity-dependently enhanced with time after Gd-DTPA aerosol inhalation regardless of the respiratory SI changes, except for three animals with the fastest breathing rate. The averaged maximal relative lung SI increase against the baseline in the successful animals was significantly greater in the slowly and deeply breathing animals than in the fast and shallow breathing animals, regardless of the difference in Gd-concentration (100 mmol Gd/L: 153.3% +/- 69.7% vs. 54.2% +/- 23%; P < 0.001; and 200 mmol Gd/L: 189.7% +/- 68.0% vs. 75.6% +/- 42.2%; P < 0.0001, respectively). There was an additional enhancement of 382% +/- 101 in the ventral lung and 722% +/- 160 in the dorsal lung on the pulmonary arterial phase perfusion image even in the slowly and deeply breathing animals who inhaled 200-mmol-Gd/L aerosol, and the enhancement effect was significantly greater compared with that with the aerosol (P < 0.0001). The ventilation- and perfusion-weighted images clearly defined the regionally matched perfusion-ventilation deficits in all the AO models, and the regionally mismatched perfusion-ventilation in all the PE models. CONCLUSION: Gd-based aerosol can provide efficient lung enhancement in spontaneously and adequately breathing animals, using a relatively noninvasive aerosol delivery system. The combined use of Gd-based perfusion MR imaging may be acceptable for defining regionally impaired function associated with acute AO and PE.     

Potential of noncontrast electrocardiogram-gated half-fourier fast-spin-echo magnetic resonance imaging to monitor dynamically altered perfusion in regional lung

RATIONALE AND OBJECTIVES: The potential of a noncontrast, electrocardiography (ECG)-gated fast-spin-echo (FSE) MR imaging (MRI) to monitor dynamically altered regional lung perfusion was assessed in acute and temporal pulmonary embolic and airway obstruction dog models. MATERIALS AND METHODS: After acquisition of ECG-gated multiphase FSE MR images during one cardiac cycle, the two phase images of the minimal lung signal intensity (SI) during systole and the maximal SI during diastole were acquired in the lower lung levels in six normal dogs, in 13 dogs before and for 35 minutes after temporal microvascular embolization in regional lungs with gradually degradable starch microspheres of spherex, and in 12 dogs before and for 45 minutes after bronchial occlusion with a balloon catheter. In three of the 13 embolic models, the opposite lung areas, however, were permanently embolized with enbucrilate. Subtraction between the diastolic and systolic images yielded a perfusion-weighted image. The results were compared with a gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced dynamic perfusion MRI, which was subsequently performed after the ECG-gated MRI in each animal. RESULTS: The multiphase FSE images provided cardiac-dependent pulsatile lung SI changes, and the subtracted perfusion-weighted images provided a uniform perfusion map in normal lungs. In all the embolic models, the subtracted perfusion-weighted images showed gradual disappearance of the spherex-induced perfusion deficits, while the enbucrilate-induced perfusion deficits persistently remained in the three animals. In all airway obstruction models, these images showed gradually decreased perfusion in the hypoventilated areas. These results were consistent with the matched Gd-DTPA-enhanced pulmonary arterial perfusion phase images in each animal. CONCLUSION: This noncontrast perfusion MRI may have excellent potential for continuously monitoring dynamically changed regional lung perfusion within a short time on its high spatial resolution cross-sectional images.     

A resected case of solitary fibrous tumor of the pleura

A 45-year-old female with solitary fibrous tumor (SFT) of the pleura was reported. Chest X-ray and CT scan on admission showed a large tumor in the right thoracic cavity. A preoperative needle biopsy was performed. The microscopic appearance of biopsied specimen revealed many spindle cells. And an immunohistochemical study was positive for CD 34 and negative for keratin, epithelial membrane antigen, alpha-smooth muscle actin, S-100 protein. So SFT was strongly suspected and an operation was performed. A tumor arised from the visceral pleura of right middle lobe and was pedunculated. The tumor was 13 x 10 x 7.5 cm in size. An immunohistochemical study of the tumor was positive for CD 34, and negative for SMA, ki-67. From these immunohistochemical stainings and microscopic findings, the tumor was diagnosed as SFT. An immunohistochemical study of the tumor seems to be very useful for the diagnosis of SFT.     

Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.     

Nonspecific interstitial pneumonia: correlation between thin-section CT findings and pathologic subgroups in 55 patients

PURPOSE: To characterize thin-section computed tomographic (CT) findings of pathologic subgroups of nonspecific interstitial pneumonia (NIP) in a sizeable number of patients. MATERIALS AND METHODS: The study included 55 cases of pathologically proven NIP. The 55 cases were categorized histologically into four grades: grade 1, interstitial inflammation without fibrosis (n = 6); grade 2, interstitial inflammation predominating over fibrosis (n = 16); grade 3, fibrosis predominating over inflammation (n = 5); and grade 4, fibrosis only (n = 28). Two independent observers evaluated the presence, extent, and distribution of various CT findings. Thin-section CT findings and histologic grades were compared by using the Spearman rank correlation coefficient. Observer agreement was assessed. RESULTS: Areas with ground-glass attenuation and architectural distortion were present in all 55 patients. Traction bronchiectasis and intralobular reticular opacities were seen in 52 and 48 patients, respectively. The extent of traction bronchiectasis (r = 0.68; P <.001) and intralobular reticular opacities (r = 0.35; P <.05) correlated with the histologic grade. Honeycombing was seen in 12 (43%) of 28 patients with grade 4 NIP and in three (11%) of the remaining 27 patients (chi(2) test, P <.001). There was good agreement between the observers for the presence (kappa = 0.7-1.0) and extent (Spearman rank correlation; r = 0.87-0.98; P <.001) of various abnormalities. CONCLUSION: The extent of traction bronchiectasis and intralobular reticulation at thin-section CT correlates with increased fibrosis in NIP. Honeycombing is seen almost exclusively in patients with fibrotic NIP.     

Mechanism of anemia associated with autonomic dysfunction in rats

The aim of this study was to elucidate the mechanism of anemia associated with autonomic dysfunction in rats. Using 6-hydroxydopamine (6-OHDA)-treated sympathectomized rats, changes in systolic blood pressure, plasma catecholamine levels, hemograms, erythropoietin (EPO) secretion, and beta-adrenergic receptors on erythrocytes were monitored, and compared with desipramine- and 6-OHDA-treated, and control rats. In 6-OHDA-treated rats, systolic blood pressure and plasma catecholamine levels significantly decreased from 7 days after 6-OHDA administration, returning to the control values on day 28. Hemoglobin (Hb), hematocrit (Hct) and red blood cell (RBC) levels significantly decreased from day 14 to day 28, and reached normal values after day 35, but neither corpuscular constants nor white blood cell (WBC) levels changed after anemia occurred. Administration of desipramine 1 day before 6-OHDA injection prevented anemia. EPO levels did not elevate, even after bloodletting to load anemia, and the EPO circadian rhythm was irregular in 6-OHDA-treated rats. beta-adrenergic receptors measured using 125I-cyanopindolol (CYP) significantly decreased from day 7 to day 28, and reached normal values after day 35. These results suggest that irregular EPO secretion via disordered autonomic nerves may induce anemia in patients with autonomic disorders.     

Corticofugal modulation of duration-tuned neurons in the midbrain auditory nucleus in bats

Animal sounds, as well as human speech sounds, are characterized by multiple parameters such as frequency, intensity, duration, etc. The central auditory system produces neurons tuned to particular durations and frequencies of sounds emitted by a species. In bats, "duration-tuned" neurons are mostly sensitive to short durations and high frequencies of sounds used for echolocation. They are scattered in the frequency maps of the inferior colliculus and auditory cortex. We found that electric stimulation of cortical duration-tuned neurons modulates collicular duration-tuned neurons in both duration and frequency tuning only when collicular and cortical neurons paired for studies are within +/-4 ms in best duration and within +/-6 kHz in best frequency. There are four types of modulations: sharpening or broadening of duration tuning, and lengthening or shortening of best duration. Sharpening is observed in "matched" collicular neurons whose best durations are the same as those of stimulated cortical neurons, and it is accompanied by augmentation of the auditory responses at their best durations. The other three types of modulations are observed in "unmatched" collicular neurons whose best durations are different from those of stimulated cortical neurons. Lengthening or shortening of best duration is linearly related to the amount of the difference in best duration between collicular and cortical neurons. Corticofugal modulation is specific and systematic according to relationships in both duration and frequency between stimulated cortical and recorded collicular neurons.     

Open-lung Protective Ventilation with Pressure Control Ventilation, High-frequency Oscillation, and Intratracheal Pulmonary Ventilation Results in Similar Gas Exchange, Hemodynamics, and Lung Mechanics

Background: Pressure control ventilation (PCV), high-frequency oscillation (HFO), and intratracheal pulmonary ventilation (ITPV) may all be used to provide lung protective ventilation in acute respiratory distress syndrome, but the specific approach that is optimal remains controversial.

Methods: Saline lavage was used to produce acute respiratory distress syndrome in 21 sheep randomly assigned to receive PCV, HFO, or ITPV as follows: positive end-expiratory pressure (PCV and ITPV) and mean airway pressure (HFO) were set in a pressure-decreasing manner after lung recruitment that achieved a ratio of Pao2/Fio2 > 400 mmHg. Respiratory rates were 30 breaths/min, 120 breaths/min, and 8 Hz, respectively, for PCV, ITPV, and HFO. Eucapnia was targeted with peak carinal pressure of no more than 35 cm H2O. Animals were then ventilated for 4 h.

Results: There were no differences among groups in gas exchange, lung mechanics, or hemodynamics. Tidal volume (PCV, 8.9 +/- 2.1 ml/kg; ITPV, 2.7 +/- 0.8 ml/kg; HFO, approximately 2.0 ml/kg) and peak carinal pressure (PCV, 30.6 +/- 2.6 cm H2O; ITPV, 22.3 +/- 4.8 cm H2O; HFO, approximately 24.3 cm H2O) were higher in PCV. Pilot histologic data showed greater interstitial hemorrhage and alveolar septal expansion in PCV than in HFO or ITPV.