Prognostic value of the serum creatinine/cystatin C ratio in patients with chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, characterized by skeletal muscle atrophy and physical inactivity, is a manifestation of chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. The serum creatinine (Cr)/cystatin C (CysC) ratio has been proposed as a marker of sarcopenia, given its correlation with total skeletal muscle mass, and as a prognostic indicator in COPD. This study aimed to evaluate the usefulness of the serum Cr/CysC ratio as a prognostic determinant in these patients. METHODS: A total of 124 outpatients with COPD were enrolled in this study. Their serum Cr and CysC levels were measured. Survival time analyses were conducted to compare mortality rates between the low and high serum Cr/CysC ratio groups. Multivariate analysis was performed to investigate the association between various factors. RESULTS: Using a serum Cr/CysC cut-off value of 0.885, the mortality rate (per 1000 person-years) for overall mortality was significantly higher in the low serum Cr/CysC ratio group (69.2 versus 28.6; hazard ratio, 2.47; 95% confidence interval, 1.06-5.79; p < 0.05). Similarly, the mortality rate due to respiratory disease was also higher (37.8 versus 8.2; hazard ratio, 4.68; 95% confidence interval, 1.05-20.9; p < 0.05). Multivariate Cox proportional hazards analysis revealed that serum Cr/CysC was an independent risk factor for respiratory disease mortality, regardless of age and airflow limitations. CONCLUSIONS: The serum Cr/CysC ratio could be a valuable clinical parameter for identifying sarcopenia and severe airflow obstruction. The study findings highlight the utility of this ratio as a prognostic predictor in patients with COPD.

Serum Derivatives of Reactive Oxygen Metabolites are Associated with Severity of Chronic Obstructive Pulmonary Disease and Affected by a p53 Gene Polymorphism.

Purpose: Oxidative stress is known to activate tumor suppressor p53, which inhibits cell cycle progression and induces apoptosis. Levels of p53 in lung tissues from patients with chronic obstructive pulmonary disease (COPD) are increased compared with levels in nonsmokers or smokers without emphysema. A polymorphism in p53 codon 72 (rs1042522) is associated with emphysematous changes in patients with COPD. However, whether oxidative stress in the serum is associated with the p53 polymorphism and disease severity in COPD patients is unclear. Patients and Methods: A total of 251 patients with a history of smoking more than 10 pack-years were enrolled in this study, and serum levels of derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and d-ROMs/BAP ratio (oxidative stress index; OSI) were measured. The percent low-attenuation area (LAA%) and cross-sectional area of the erector spinae muscles (ESMCSA) at the Th12 level were calculated from chest high-resolution computed tomography images. p53 codon 72 C/G genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: In patients carrying the p53 GG genotype, LAA% was significantly higher than in those carrying the CC genotype. d-ROM levels and OSI were associated with COPD severity and correlated with airflow limitation and markers of muscle atrophy (ESMCSA and creatinine/cystatin C ratio). Associations between markers of oxidative stress and COPD severity were observed primarily in patients carrying the p53 codon 72 GG genotype. Conclusion: Susceptibility to pulmonary emphysema and responses to oxidative stress may be affected by the p53 gene polymorphism.

Serum Creatinine/Cystatin C Ratio Associated with Cross-Sectional Area of Erector Spinae Muscles and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: Muscle atrophy is a major clinical feature of chronic obstructive pulmonary disease (COPD) and is considered a predictor of mortality in COPD patients. Recently, the cross-sectional area (CSA) of the erector spinae muscles measured by chest computed tomography (CT) scans (ESMCSA) has been reported as a clinical parameter reflecting disease severity and future prognosis in patients with COPD. In addition, the serum creatinine (Cr)/cystatin C (CysC) ratio has been considered a quantitative marker of residual muscle mass, because serum Cr levels are affected by muscle mass, and correction by CysC counteracts the effect of renal function on serum Cr levels. The purpose of this study was to assess whether the serum Cr level corrected by serum CysC can be used as a predictive marker of pulmonary function and disease severity in patients with COPD. PATIENTS AND METHODS: A total of 99 patients without COPD and 201 patients with COPD, with a smoking history of more than 10 pack-years were enrolled in this study, and serum Cr and CysC levels were measured. On chest high-resolution CT images, %low attenuation area (LAA%) (≤960 Hounsfield units (HU)) and ESMCSA at the Th12 level were identified. RESULTS: There was a significant correlation between the ESMCSA and the Cr/CysC ratio. The Cr/CysC ratio was significantly associated with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values, especially in former smokers. CONCLUSION: The serum Cr/CysC ratio could be a convenient substitute for the measurement of muscle atrophy and pulmonary function testing in patients with COPD.

Trafficking of newly synthesized surfactant protein B to the lamellar body in alveolar type II cells.

Lung surfactant accumulates in the lamellar body (LB) via not only the secretory (anterograde) pathway but also the endocytic (retrograde) pathway. Our previous studies suggested that the major surfactant components, phosphatidylcholine and surfactant protein A take independent trafficking routes in alveolar type II cells. Thus, trafficking of surfactant protein B (SP-B), a major hydrophobic surfactant apoprotein, should be re-evaluated by a straightforward method. Radiolabeling of cells and subsequent cell fractionation were employed to pursue the sequential trafficking of newly synthesized SP-B in rabbit alveolar type II cells. The LB fraction was prepared by gradient ultracentrifugation. Immunoprecipitation from the culture medium, total cells, and LB fraction was carried out with anti-SP-B antibody. Newly synthesized [35S]-pro-SP-B (~ 42 kDa) was detected in the cells after 1 h. An ~ 8-kDa mature form of [35S]-SP-B was detected in the cells after 3 h and in the LB after 6 h. Mature [35S]-SP-B was predominant in the cells after 24 h, and the dominant portion was present in the LB. In contrast, only a small amount of mature [35S]-SP-B was present in the culture medium. Molecular processing of ~ 42 kDa [35S]-pro-SP-B and transport to the LB was inhibited by brefeldin A, which disassembles the Golgi apparatus. These results suggest that newly synthesized SP-B is sorted to the LB via the Golgi and stored until exocytosis. This pathway is distinct from the pathways reported for phosphatidylcholine and surfactant protein A.

[Resection of Metastatic Lung Tumor with a Right Displaced Segmental Bronchus (B1+3);Report of a Case].

We experienced a resected case of metastatic lung tumor with a right displaced segmental bronchus (B1+3). The patient was an 82-year-old woman who had a history of surgery for transverse colon cancer. A chest computed tomography (CT) scan revealed a nodular shadow with an irregular margin( 3.1 cm in diameter) in the right upper lobe, which was suspected of a primary lung cancer. Chest CT and bronchoscopy revealed B1+3 displaced segmental bronchus. Thoracoscope-assisted right upper lobectomy was performed for diagnostic and therapeutic purposes. The pathological diagnosis was a metastatic lung tumor from the transverse colon cancer.

[Lung Adenocarcinoma Combined with Minute Pulmonary Meningothelial-like Nodule (MPMN) in Young Patient;Report of a Case].

We report a rare case of lung adenocarcinoma combined with minute pulmonary meningothelial-like nodule (MPMN) in a young adult. A 39-year-old woman was referred to our department for abnormal shadow of the right lower lobe. Chest computed tomography (CT) showed a mass shadow, 11 mm in size, in right S6. Since fluorodeoxyglucose-positron emission tomography (FDG-PET) demonstrated a lesion with FDG activity, with an increased uptake value of 2.2, this lesion was suspected to be a lung cancer. Wedge resection of right S6 was performed via thoracoscopy. The intraoperative pathological diagnosis was invasive lung adenocarcinoma, and additional right S6 segmentectomy and lymph node dissection (ND1a) was performed. The final pathological diagnosis of the tumor was adenocarcinoma of the lung, and MPMN was incidentally found by pathology in reseced specimen.

ADRB2 gene polymorphism and emphysema heterogeneity can modulate bronchodilator response in patients with emphysema.

BACKGROUND: Genetic variation in the ß2-adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to ß2-agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies. METHODS: The BDR (induced by 20 µg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from -100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema. CONCLUSION: Combination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of ß2-adrenergic receptor agonist treatment in patients with COPD and emphysema.

Exogenous gene transfer of Rab38 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats.

BACKGROUND: Rab38 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab38 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We previously showed that Long Evans Cinnamon (LEC) rats, one strain of the Ruby rats, developed aberrant lung surfactant homeostasis with remarkably enlarged lamellar bodies in alveolar type II cells. METHODS: A replication-deficient recombinant adenovirus expressing rat Rab38 (Ad-Rab38) was constructed. Alveolar type II cells were isolated from the LEC rats and tested for lung surfactant phosphatidylcholine secretion. The rats were also examined whether exogenous expression of Ad- Rab38 could rescue the altered lung surfactant homeostasis in the lungs. RESULTS: Isolated type II cells infected with Ad-Rab38 exhibited improved secretion patterns of [3H]phosphatidylcholine, i.e. increased basal hyposecretion and decreased agonist-induced hypersecretion. Endobronchial administration of Ad-Rab38 improved the morphology of type II cells and lamellar bodies, reducing their sizes close to those of wild-type rats. The increased amounts of phosphatidylcholine and surfactant protein B in the lamellar body fractions were decreased in the Ad-Rab38 infected lungs. CONCLUSIONS: These results provide strong evidence that the aberrant lung surfactant homeostasis in the LEC rats is caused by Rab38 deficit, and suggest that endobronchial delivery of the responsive transgene could be an effective method to ameliorate the abnormal lung phenotype in the animal model of HPS.

p53 Signaling Pathway Polymorphisms Associated With Emphysematous Changes in Patients With COPD.

BACKGROUND: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. METHODS: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. RESULTS: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. CONCLUSIONS: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.

Sirt1 expression is associated with CD31 expression in blood cells from patients with chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34+ progenitor cells to examine whether these genes are associated with COPD development. METHODS: This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34+ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR. RESULTS: The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells. CONCLUSION: Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.

A critical role of Dectin-1 in hypersensitivity pneumonitis.

OBJECTIVES AND DESIGN: Hypersensitivity pneumonitis (HP) is a pulmonary disease caused by repeated exposure to various aspiration antigens, including bacteria and fungi. Although TLRs are known to be required for the generation of HP triggered by bacteria, the significance of fungal receptors remains unclear. The present study aimed to investigate whether Dectin-1 and Dectin-2 contribute to the development of experimental HP triggered by the fungus Trichosporon asahii (T. asahii) that causes summer-type HP. MATERIALS AND METHODS: We investigated the binding between Dectin-Fc protein and T. asahii by a dot blot assay. We performed the histological and flow cytometric analysis in the HP model using Dectin-1-deficient (Dectin-1(-/-)) and Dectin-2(-/-) mice. We also investigated Th17/Th1 responses in lung cells, and measured an IL-17-promoting cytokine IL-23 from bone marrow-derived dendritic cells (BMDCs) by ELISA. RESULTS: Dectin-1 bound more strongly to T. asahii than Dectin-2. Dectin-1(-/-) mice barely developed HP, whereas both wild-type mice and Dectin-2(-/-) mice developed similar lung diseases. Dectin-1 deficiency decreased the infiltration of neutrophils and monocyte-derived macrophages and repressed the expansion of lung CD4(+)IL-17A(+) cells. The production of IL-23 p19 was reduced in Dectin-1(-/-) BMDCs. CONCLUSIONS: These data suggested Dectin-1 plays a critical role in the development of fungus-induced HP.

Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks.

Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

Pulmonary vascular and airway responses to systemic vasoconstrictors in anesthetized BALB/c mice.

There is no systematic study in which the effects of vasoactive substances were investigated on pulmonary vascular resistance (PVR) in in vivo mouse by directly measuring cardiac output and the inflow and outflow pressures in the pulmonary circulation. We determined the responses of PVR, total peripheral resistance (TPR), and airway pressure (AWP) to angiotensin II, endothelin-1, vasopressin, phenylephrine, and thromboxane A2 analog U46619 in anesthetized BALB/c mice. Pulmonary arterial pressure, left atrial pressure (LAP), and aortic blood flow were measured. TPR increased dose-dependently in response to consecutive administration of all vasoconstrictors except vasopressin which reduced TPR at the highest dose of 100 nmol/kg. At high doses of vasoconstrictors, pulmonary arterial pressure and AWP increased due to increased LAP, as demonstrated by the separate LAP elevation experiments. When LAP transiently increased at high doses, PVR did not increase but decreased. Nonetheless, enodothelin-1, angiotensin II, and U46619 increased PVR. Vasopressin at 100 nmol/kg increased AWP without LAP elevation. In conclusion, the high doses of the vasoconstrictors studied here exert indirectly a transient pulmonary vasodilatory and AWP increasing actions due to pulmonary congestion evoked by strong systemic vasoconstriction. Nevertheless, enodothelin-1, angiotensin II, and U46619 cause pulmonary vasoconstriction, and vasopressin constricts airway in anesthetized BALB/c mice.

A case of IgG4-related kidney disease complicated by eosinophilic lung disease.

IgG4-related disease is a systemic chronic inflammatory disorder characterized by a high blood level of IgG4 and the organ injuries by marked infiltration of IgG4-positive plasma cells and fibrosis. A 71-year-old male was hospitalized for a cough, malaise and anorexia. IgG4-related disease was suspected due to marked elevation of the serum IgG4 level. However, on lung biopsy, only eosinophil infiltration was demonstrated with no plasma cell infiltration. Otherwise abdominal contrast-enhanced CT showed mild enlargement of the bilateral kidneys and many differed contrasted areas and FDG PET-CT. Moreover, renal biopsy specimens showed typical tubulointerstitial nephritis with a large number of IgG4-positive plasma cells infiltration (the IgG4/IgG-positive cell rate, 89 %) and fibrosis. We diagnosed this patient as typical IgG4-related kidney disease. He was treated by the moderate dose of prednisolone (0.8 mg/kg/day) alone, and showed prompt response in the clinical condition, and both the lung and kidney lesions. In this case, it was useful for diagnosis of IgG4-related diseases to evaluate an image such as abdominal contrast-enhanced CT and FDG PET-CT. Our case might be one of the possible patterns of IgG4-related lung diseases. In addition, we thought that there might be an association between hypereosinophilia and IgG4-related kidney disease.

Adenovector-mediated gene transfer of lysophosphatidylcholine acyltransferase 1 attenuates oleic acid-induced acute lung injury in rats.

OBJECTIVE: Lysophosphatidylcholine is generated through the hydrolysis of phosphatidylcholine by phospholipase A2 and reversely converted to phosphatidylcholine by lysophosphatidylcholine acyltransferase 1. Although lysophosphatidylcholine is a potent proinflammatory mediator and increased in several types of acute lung injuries, the role of lysophosphatidylcholine acyltransferase 1 has not yet been addressed. We aimed to investigate whether the exogenous expression of lysophosphatidylcholine acyltransferase 1 could attenuate acute lung injury. DESIGN: Randomized, prospective animal study, including in vitro primary cell culture test. SETTING: University medical center research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Recombinant adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1 or lacZ (Ad-lacZ) as a control was constructed. Alveolar type II cells were isolated from rats and cultured on tissue-culture inserts. Rats were pretreated with an endobronchial administration of the recombinant adenovirus. One week later, they were IV injected with oleic acid. The lungs were examined 4 hours post oleic acid. MEASUREMENTS AND MAIN RESULTS: Adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1-infected alveolar type II cells showed lower lysophosphatidylcholine levels and a decreased percentage of cell death compared with Ad-lacZ-infected cells or noninfected cells after exposure to hydrogen peroxide for 1 hour. Compared with Ad-lacZ plus oleic acid-treated lungs, adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1 plus oleic acid-treated lungs showed a lower wet-to-dry lung weight ratio, a higher lung compliance, lower lysophosphatidylcholine contents, higher phosphatidylcholine contents, and a lower apoptosis ratio of alveolar type II cells. Histological scoring revealed that the adenoviruses carrying complementary DNA encoding lysophosphatidylcholine acyltransferase 1-treated lungs developed oleic acid-induced lung injuries that were attenuated compared with those of Ad-lacZ-treated lungs. CONCLUSIONS: Exogenous expression of lysophosphatidylcholine acyltransferase 1 protects alveolar type II cells from oxidant-induced cell death in vitro, and endobronchial delivery of a lysophosphatidylcholine acyltransferase 1 transgene effectively attenuates oleic acid-induced acute lung injury in vivo. These results suggest that lysophosphatidylcholine acyltransferase 1 plays a protective role in acute lung injury.

A three-microphone acoustic reflection technique using transmitted acoustic waves in the airway.

The acoustic reflection technique noninvasively measures airway cross-sectional area vs. distance functions and uses a wave tube with a constant cross-sectional area to separate incidental and reflected waves introduced into the mouth or nostril. The accuracy of estimated cross-sectional areas gets worse in the deeper distances due to the nature of marching algorithms, i.e., errors of the estimated areas in the closer distances accumulate to those in the further distances. Here we present a new technique of acoustic reflection from measuring transmitted acoustic waves in the airway with three microphones and without employing a wave tube. Using miniaturized microphones mounted on a catheter, we estimated reflection coefficients among the microphones and separated incidental and reflected waves. A model study showed that the estimated cross-sectional area vs. distance function was coincident with the conventional two-microphone method, and it did not change with altered cross-sectional areas at the microphone position, although the estimated cross-sectional areas are relative values to that at the microphone position. The pharyngeal cross-sectional areas including retropalatal and retroglossal regions and the closing site during sleep was visualized in patients with obstructive sleep apnea. The method can be applicable to larger or smaller bronchi to evaluate the airspace and function in these localized airways.

[Assessment of treatment effect for acromegaly with sleep disordered breathing].

Acromegaly is caused by excessive secretion of growth hormone (GH) and presents with a variety of clinical manifestations, including facial disfigurement and abnormally large hands and feet, as well as diabetes mellitus, hypertension, and sleep-disordered breathing (SDB). Although SDB is known to be associated with serious symptoms, there have been few study reports, and no clear consensus has been reached regarding the method of assessment of individual treatments. We report herein on the results of surgical intervention with transsphenoidal surgery (TSS) for acromegaly and assessment of the treatment effect after the intervention. We studied 6 patients who received a diagnosis of acromegaly complicated with SDB and underwent TSS at our hospital. Polysomnography (PSG) was performed before and after TSS, and the polysomnograms were analyzed. We also examined changes in the levels of GH and insulin-like growth factor-1 (IGF-1) on blood biochemistry. In 6 cases of acromegaly with SDB, we were able to confirm endocrinologic improvement of TSS with blood biochemistry. However there was no meaningful improvement in the PSG index for SDB.

Nitric oxide and ß(2)-adrenoceptor activation attenuate pulmonary vasoconstriction during anaphylactic hypotension in anesthetized BALB/c mice.

Systemic anaphylaxis accompanies pulmonary vasoconstriction and bronchoconstriction, which may contribute to increased right heart afterload, and finally anaphylactic hypotension. However, the pulmonary response to anaphylaxis is not known in mice. We determined the pulmonary vascular and bronchial response to systemic anaphylaxis in anesthetized BALB/c mice. We also clarified the roles of ß-adrenoceptors, nitric oxide, and cyclooxygenase metabolites in these responses. Anaphylaxis was induced by an intravenous injection of the ovalbumin antigen into open-chest artificially ventilated sensitized mice. Mean arterial pressure, systolic pulmonary arterial pressure, central venous pressure, airway pressure, and aortic blood flow were continuously measured. In sensitized control mice, mean arterial pressure, and aortic blood flow substantially decreased soon after the antigen injection, while systolic pulmonary arterial pressure and airway pressure did not increase. In contrast, in mice pretreated with either the ß(2)-adrenoceptor antagonist ICI 118,551 (0.2 mg/kg; n = 6), or L-NAME (50 mg/kg; n = 6), but not with the ß(1)-adrenoceptor antagonist atenolol (2 mg/kg; n = 6) or indomethacin (5 mg/kg; n = 6), systolic pulmonary arterial pressure increased by 7 mmHg at 1.5 min after antigen. In L-NAME pretreated mice, pulmonary hypertension was sustained over 30 min of the experimental period. Airway pressure did not significantly change after antigen in any mice studied. In conclusion, pulmonary response to systemic anaphylaxis does not increase the right heart afterload and, therefore, may not contribute to the initial decrease in venous return and anaphylactic hypotension in anesthetized mice. ß(2)-adrenoceptor activation and nitric oxide, but not ß(1)-adrenoceptor activation or cyclooxygenase metabolites, attenuate the antigen-induced pulmonary vasoconstriction.

Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome.

Several Long-Evans rat substrains carrying the phenotype of oculocutaneous albinism and bleeding diathesis are a rat model of Hermansky-Pudlak syndrome (HPS). The mutation responsible for the phenotype (Ruby) was identified as a point mutation in the initiation codon of Rab38 small GTPase that regulates intracellular vesicle transport. As patients with HPS often develop life-limiting interstitial pneumonia accompanied by abnormal morphology of alveolar type II cells, we investigated lung surfactant system in Long-Evans Cinnamon rats, one strain of the Ruby rats. The lungs showed conspicuous morphology of type II cells containing markedly enlarged lamellar bodies. Surfactant phosphatidylcholine and surfactant protein B were increased in lung tissues and lamellar bodies but not in alveolar lumen. Expression levels of mRNA for surfactant proteins A, B, C, and D were not altered. Isolated type II cells showed aberrant secretory pattern of newly synthesized [(3)H]phosphatidylcholine, i.e., decreased basal secretion and remarkably amplified agonist-induced secretion. [(3)H]phosphatidylcholine synthesis and uptake by type II cells were not altered. Thus Rab38-deficient type II cells appear to carry abnormality in lung surfactant secretion but not in synthesis or uptake. These results suggest that aberrant lung surfactant secretion may be involved in the pathogenesis of interstitial pneumonia in HPS.

Hepatic microvascular pressure during anaphylactic shock in anesthetized rats.

OBJECTIVE: Hepatic venoconstriction plays a significant role in anaphylactic hypotension in anesthetized rats. The purpose of this study is to determine whether the primary site of anaphylactic venoconstriction in the liver venous circulation occurs prior to or distal to the sinusoidal capillaries. We also determined whether the hepatic blood volume is increased during anaphylactic hypotension. METHODS: We measured, using a servo-null micropipette pressure-measuring system, the hepatic venular transmural pressure (P micro hv) at the liver surface of anesthetized rats sensitized with the antigen of ovalbumin (1 mg). We also measured the liver lobe thickness, using the ultrasonic crystal dimension measuring system. Anaphylactic hypotension was induced by an intravenous injection of 0.6 mg ovalbumin. RESULTS: When the antigen was injected, the systemic arterial pressure decreased profoundly from 118+/-9 to 45+/-4 mm Hg, which was accompanied by an increase in Ppv and P micro hv: P micro hv only transiently increased from 3.1+/-0.9 to 8.8+/-1.5 cm H(2)O at 1 min and then rapidly returned to the baseline within 2 min, when Ppv continued to increase and reached the peak of 36+/-7 cm H(2)O at 3.5 min after antigen. This greater increase in Ppv-to-P micro hv gradient than that in P micro hv-to-Pcv gradient after antigen indicated that the constriction of the portal veins and the sinusoids much predominates over that of the hepatic veins. Along with this hepatic pre- and sinusoidal constriction, the liver lobe thickness significantly decreased by 4% after antigen. CONCLUSION: Pre-sinusoidal constriction during anaphylactic shock in anaesthetized rats increased the portal venous pressure while the hepatic venular pressure only increased slightly and transiently. This predominant pre-sinusoidal constriction is accompanied by a decrease in liver volume.