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C Clerici

Publications and source records attributed to C Clerici.

At least 19 recordsLinked to original sources
PubMed2000

Hypoxia regulates gene expression of alveolar epithelial transport proteins.

Alveolar hypoxia occurs during ascent to high altitude but is also commonly observed in many acute and chronic pulmonary disorders. The alveolar epithelium is directly exposed to decreases in O(2) tension, but a few studies have evaluated the effects of hypoxia on alveolar cell function. The alveolar epithelium consists of two cell types: large, flat, squamous alveolar type I and cuboidal type II (ATII). ATII cells are more numerous and have a number of critical functions, including transporting ions and substrates required for many physiological processes. ATII cells express 1) membrane proteins used for supplying substrates required for cell metabolism and 2) ion transport proteins such as Na(+) channels and Na(+)-K(+)-ATPase, which are involved in the vectorial transport of Na(+) from the alveolar to interstitial spaces and therefore drive the resorption of alveolar fluid. This brief review focuses on gene expression regulation of glucose transporters and Na(+) transport proteins by hypoxia in alveolar epithelial cells. Cells exposed to severe hypoxia (0% or 3% O(2)) for 24 h upregulate the activity and expression of the glucose transporter GLUT-1, resulting in preservation of ATP content. Hypoxia-induced increases in GLUT-1 mRNA levels are due to O(2) deprivation and inhibition of oxidative phosphorylation. This regulation occurs at the transcriptional level through activation of a hypoxia-inducible factor. In contrast, hypoxia downregulates expression and activity of Na(+) channels and Na(+)-K(+)-ATPase in cultured alveolar epithelial cells. Hypoxia induces time- and concentration-dependent decreases of alpha-, beta-, and gamma-subunits of epithelial Na(+) channel mRNA and beta(1)- and alpha(1)-subunits of Na(+)-K(+)-ATPase, effects that are completely reversed after reoxygenation. The mechanisms by which O(2) deprivation regulates gene expression of Na(+) transport proteins are not fully elucidated but likely involve the redox status of the cell. Thus hypoxia regulates gene expression of transport proteins in cultured alveolar epithelial type II cells differently, preserving ATP content.

Animals↗
PubMed1999

Hypoxia increases glyceraldehyde-3-phosphate dehydrogenase transcription in rat alveolar epithelial cells.

Alveolar epithelial type II (ATII) cells are particularly hypoxia-tolerant in vitro. As one of the mechanisms of hypoxia tolerance is the induction of certain proteins, one of which is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), we investigated whether hypoxia modified GAPDH expression in ATII cells. Hypoxia induced a time- and O(2) concentration-dependent accumulation of GAPDH mRNA in cultured rat ATII cells (2- to 3-fold the normoxic value after 18 h in 0% O(2)), an effect completely reversed by reoxygenation. GAPDH mRNA induction was accounted for by an increase in GAPDH gene transcription during hypoxia with no change in mRNA stability. GAPDH protein synthesis increased 3- to 4-fold after 18 h of 0% O(2), while the GAPDH protein steady-state level rose by 75%. GAPDH enzymatic activity in hypoxic cell homogenates increased by 45%. These results indicate that hypoxia induces GAPDH expression in ATII cells through an increase in transcription.

Animals↗
PubMed1999

Halothane stimulates a Na+H+ antiporter involved in the regulation of intracellular pH in alveolar epithelial cells.

UNLABELLED: Changes in intracellular pH (pHi) of alveolar type II (ATII) cells have been involved in the pathophysiology of pulmonary edema. ATII cells have evolved several ions transporters to regulate their pHi, including a Na+H+ antiporter. Because halothane alters the activity of ion transporters in various cells types, it may also affect the activity of this Na+H+ antiporter. This study was performed 1) to characterize a Na+H+ antiporter in a model of ATII cells and 2) to investigate the effect of halothane on the activity of this antiporter. ATII cells were obtained from primary rat ATII cells transfected with a mutant of simian virus SV40 large T antigen (SV40-T2), and their pHi was monitored using the pH-sensitive fluorescent probe 2'-7' (bis carboxyethyl)-5(6')-carboxyfluorescein. We demonstrated in vitro that 1) a Na+H+ antiporter (apparent Km 6.8 +/- 3.4 mM, Vmax 0.0105 +/- 0.0013 delta UpHi/s) regulates the pHi of SV40-T2 cells and 2) at clinically relevant concentrations (10(-3) to 10(-5) M) and for a short exposure duration (60 min), halothane enhances the activity of this antiporter. Because ATII cell acidification has been associated with alterations in the alveolar epithelial barrier, halothane-induced intracellular alkalinization might exhibit some protective effect in clinical situations, such as aspiration pneumonia. IMPLICATIONS: In vitro, halothane induces an intracellular alkalinization of pneumocytes II via the activation of a Na+H+ antiporter. Because acidification of these cells has been associated with alterations in the alveolar epithelial barrier, halothane might exhibit some protective effect in clinical situations, such as aspiration pneumonia.

Anesthetics, Inhalation↗
PubMed1999

Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells.

Alveolar epithelial cells (AEC) are directly exposed to high alveolar O(2) tension. Many pulmonary disorders are associated with a decrease in alveolar O(2) tension and AEC need to develop adaptative mechanisms to cope with O(2) deprivation. Under hypoxia, because of inhibition of oxidative phosphorylation, adenosine triphosphate supply is dependent on the ability of cells to increase anaerobic glycolysis. In this study we show that under hypoxia, primary rat AEC maintained their energy status close to that of normoxic cells through increasing anaerobic glycolysis. We therefore examined the effect of hypoxia on glucose transport and evaluated the mechanisms of this regulation. Hypoxia induced a stimulation of Na-independent glucose transport, as shown by the increase in 2-deoxy-D-glucose (DG) uptake. This increase was dependent on time and O(2) concentration: maximal at 0% O(2) for 18 h, and reversible after hypoxic cells were allowed to recover in normoxia. Concomitantly, exposure of AEC to hypoxia (18 h 0% O(2)) induced a 3-fold increase of glucose transporter GLUT1 at both protein and messenger RNA (mRNA) levels. To determine whether the increase in GLUT1 mRNA level was dependent on O(2) deprivation per se or resulted from decrease of oxidative phosphorylation, we examined in normoxic cells the effects of cobalt chloride and Na azide, respectively. Cobalt chloride (100 microM) and Na azide (1 mM) increased both mRNA levels and DG uptake, mimicking the effect of hypoxia. Electrophoretic mobility shift assays revealed a hypoxic and a cobalt chloride induction of a hypoxia-inducible factor (HIF) that bound to the sequence of nucleotides, corresponding to a hypoxia-inducible element upstream of the GLUT1 gene. AEC also expressed this factor under nonhypoxic conditions. Together, our results demonstrate that AEC increased glucose transport in response to hypoxia by regulating GLUT1 gene-encoding protein. This regulation likely occurred at the transcriptional level through the activation of an HIF, the nature of which remains to be elucidated.

Adenosine Triphosphate↗
PubMed1999

Airway obstruction in bronchial sarcoidosis: outcome with treatment.

STUDY OBJECTIVE: Airway obstruction (AO) in sarcoidosis is reported to be associated with respiratory symptoms, increased morbidity, and an increased mortality risk. Because AO in sarcoidosis may result from several causes, the therapeutic benefit of corticosteroids is difficult to determine. The aim of this study was to evaluate the therapeutic response of AO attributable to sarcoid granulomas in the bronchial wall. PATIENTS: We selected 11 patients who had sarcoidosis with AO (defined as FEV(1)/vital capacity [VC] < 70%) associated with sarcoid granulomas on an endobronchial biopsy. Exclusion criteria were history of asthma, smoker or ex-smoker, stage 4 disease, evidence of extrinsic compression by enlarged lymph nodes, and localized endobronchial stenosis seen during fiberoptic bronchoscopy. INTERVENTIONS: We compared the results of pulmonary function tests and clinical, radiologic, and biological findings at baseline with those obtained at the time of the last pulmonary function tests available, between the sixth and 12th months of treatment. Eight patients took oral corticosteroids (20 to 60 mg/d initially), one received IV methylprednisolone pulses, another took oral hydroxychloroquine, and the last one received IM methotrexate. MEASUREMENTS AND RESULTS: With treatment, FEV(1) and FEV(1)/VC significantly improved in eight patients (72%), normalized in four patients, and was unchanged in the remaining three patients. The mean FEV(1) increased from 60.8 +/- 10.8% to 76 +/- 13.7% of the predicted value (p < 0.02). VC did not change significantly. FEV(1)/VC increased from 76.1 +/- 6.4% to 87.6 +/- 10.7% of the predicted value (p < 0.01). Dyspnea on exertion and other clinical findings were attenuated in 10 patients; the chest radiograph improved in 9 patients, and normalized in 5 patients. The mean serum angiotensin-converting enzyme level decreased from 112 +/- 48 to 58 +/- 40 IU/mL (p < 0.05), and normalized in four patients. CONCLUSION: The present study indicates that AO caused by sarcoid granulomas in the bronchial wall can be either partially or completely reversed by treatment with a concomitant attenuation of pulmonary symptoms.

Administration, Oral↗
PubMed1999

[Modifications of respiratory function during pregnancy].

During pregnancy, changes in the thoracic configuration subsequent to progressive increase in the abdominal volume have a moderate effect on respiratory function. The cephalic displacement of the diaphragm reduces the expiratory reserve volume and the residual volume. The main consequence is an increase in the closing volume of the airways due to the fact that the lower residual functional capacity occurs during the tidal volume. The increase in the closing volume decreases the ventilation of the adjacent alveolar areas which could explain an increased heterogenicity of the ventilation-perfusion ratios. Increased tidal volume is almost always observed during pregnancy and is the cause of hyperventilation and a major increase in alveolar ventilation which can reach 70% of the post partum value. This hyperventilation is probably due to increased chemosensitivity of the CO2 respiratory centers induced by the hyperprogesteronism observed during pregnancy.

Estrogens↗
PubMed1998

Halothane decreases Na,K-ATPase, and Na channel activity in alveolar type II cells.

BACKGROUND: Halothane alters surfactant biosynthesis and metabolism of alveolar type II cells. In addition to synthesizing surfactant, alveolar type II cells actively transport sodium (Na) from the alveolar space to the interstitium. Na enters the cells through amiloride-sensitive Na channels or Na cotransporters and is extruded by a Na pump. The purpose of this study was to examine the effects of halothane on Na transport activities. METHODS: Epithelial type II cells from adult rat lungs were exposed to halothane concentrations of 1, 2, and 4% from 0.5-4 h. In some experiments, cells that were exposed to 1% halothane for 1 h were allowed to recover after replacement of the medium for 15 and 30 min. Na transport was then evaluated by direct measurement of radiolabeled ions uptake. In addition, the effects of halothane were assessed in the absence of extracellular calcium (Ca) with or without 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, an intracellular Ca chelating agent. RESULTS: Exposure of epithelial type II cells to halothane reduced the activity of sodium, potassium-adenosine triphosphatase, and amiloride-sensitive Na channels, whereas Na cotransporters were unchanged. The decrease in sodium, potassium-adenosine triphosphatase activity was maximal for 30 min of exposure and reached 50, 42, and 56% for halothane concentrations of 1, 2, and 4%, respectively, and did not change for longer exposure times. This effect was not prevented by either the absence of extracellular Ca or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid pretreatment. Exposure for 45 min to 1% halothane also decreased Na channel activity by 46%. These effects were completely reversible after 30 min of recovery. CONCLUSIONS: Sodium, potassium-adenosine triphosphatase, and amiloride-sensitive Na channel activities are impaired by halothane in alveolar type II cells in vitro. This inhibition could reduce transepithelial Na transport.

Alanine↗
PubMed1998

Long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a in polycythaemia vera.

We report on long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a (rIFN-alpha) in a series of 38 patients with polycythaemia vera (PV). In all patients haematocrit was first brought into the normal range by venesection; rIFN-alpha was then begun at a starting weekly dose of 9,000,000 IU. Complete response (CR) was defined as persistence of normal haematocrit without venesection and partial response (PR) as >50% reduction of phlebotomy requirement. Eleven patients (28.9%) achieved CR and 8 (21.0%) PR. Median duration of treatment for all responsive patients was 40 months; 12 patients are still responsive and under treatment after 13, 15, 25, 35, 40, 41, 43, 49, 50, 51, 52 and 52 months of therapy with rIFN-alpha. In responsive patients, rIFN-alpha also normalized leucocyte counts, platelet counts and spleen enlargement; rIFN-alpha also relieved generalized pruritus in all 10 patients displaying this symptom. Early toxicity (flu-like syndrome) was observed in 23.6% and late toxicity (severe weakness) in 13.1% of patients, requiring rIFN-alpha treatment suspension in all cases. Progression to leukaemia was observed in none of the 10 patients treated only with rIFN-alpha and in one of the 12 who received alkylating agents before enrolment in this study. According to these data, rIFN-alpha seems to be an effective and safe treatment option for PV.

Adult↗
PubMed1998

Evidence for functional ANP receptors in cultured alveolar type II cells.

Because atrial natriuretic peptide (ANP) is considered to play a role in lung physiology and pathology, our aim was to characterize natriuretic peptide receptors in cultured rat alveolar type II (ATII) cells. Guanylate cyclase A- and B-receptor but not clearance-receptor mRNAs were detected by reverse transcription-polymerase chain reaction. The absence of clearance-receptor expression in ATII cells was confirmed by competitive inhibition of ANP binding; ANP (0.1-100 nM) decreased the binding of 125I-ANP, whereas C-ANP-(4-23), a specific ligand of clearance receptors, was ineffective. ANP induced a dose-dependent increase in guanosine 3',5'-cyclic monophosphate (cGMP) production, with a threshold of 0.1 nM, whereas the response to C-type natriuretic peptide was weak and was observed only at high concentrations (100 nM). In ATII cells cultured on filters, 1) ANP receptors were present on both the apical and basolateral surfaces and 2) cGMP egression was polarized, as indicated by the greater ANP-induced cGMP accumulation in the basolateral medium, and was partially inhibited by probenecid, an organic acid transport inhibitor. Influx studies demonstrated that ANP decreased the amiloride-sensitive component of 22Na influx but did not change ouabain-sensitive 86Rb influx. In conclusion, ATII cells behave as a target for ANP. ANP activation of guanylate cyclase A receptors produces cGMP, which is preferentially extruded on the basolateral side of the cells and inhibits the amiloride-sensitive Na-channel activity.

Amiloride↗
PubMed1998

Ion transports in the middle ear epithelium.

Ion transports in the middle ear epithelium have been recently characterized. Experimental data using cell culture have found the existence of a sodium transepithelial transport that drives a water flow. This is thought to play a key role in the maintain of air-filled and fluid-free cavities. Impairment of this process is involved in the pathogenesis of secretory otitis media, which is the main cause of acquired hearing loss. Several modulations of this transport have been evidenced: (i) reactive oxygen species induced an endogenous synthesis of prostaglandin E2 (PGE2), which in turn increased the cAMP level and modulated ion transport rate; (ii) steroids increased the expression of the alpha subunit sodium channel mRNA, which changes paralleled the modulation of ion transport in the middle ear epithelium; (iii) moderate hypoxia selectively and reversibly decreased the rate of sodium transport, as a result of a parallel decrease in alpha epithelial sodium channel subunit mRNA level. These modulations may explain the course of middle ear pathology. However, the development of an in vivo model has become mandatory to assess the relevance of these data in the pathophysiology of the middle ear.

Adrenal Cortex Hormones↗
PubMed1998

5-ASA-glutamate protects rats from inflammatory bowel disease induced by intracolonic administration of trinitrobenzensulfonic acid.

BACKGROUND AND AIMS: A new amino acid derivative of 5-aminosalicylic acid, 5-ASA-glutamate, releases 5-aminosalicylic acid independently of the action of bacterial azoreductases or adapt intestinal pH. In this study, 5-ASA-glutamate was compared with sulphasalazine with respect to: 1) therapeutic action, 2) effects on the synthesis of eicosanoids, 3) regional release of 5-aminosalicylic acid in the intestine. METHODS: Colitis was induced in 29 rats by intracolonic administration of trinitrobenzensulfonic acid. Nine animals received an equal amount of saline. Three days after induction of colitis, animals were randomly assigned to equimolecular doses of 5-aminosalicylic acid as sulphasalazine (1040 mg/kg bw day) or 5-ASA-glutamate (850 mg/kg bw day) or arabic gum in water, given intragastrically. Arabic gum was also administered to animals that had received a saline enema (control group). The guts of 3 rats from the 5-ASA-glutamate group and 3 from the sulphasalazine group were used to assess regional release of 5-ASA, while in all the others, after 21 days of treatment, macroscopic and histologic lesions were assessed and eicosanoids and leukotriene determinations were performed. RESULTS: The 5-ASA-glutamate group had macroscopic (2.20 +/- 0.58) and histologic (2.80 +/- 1.24) significantly lower scores than the trinitrobenzensulfonic acid group (3.40 +/- 0.22 and 6.50 +/- 1.2 respectively). 5-ASA-glutamate group had reduced PGE2 (-31%) and TXB2 (-25%) more effectively than the sulphasalazine group. LTB4 release was not affected by 5-ASA-glutamate treatment, while sulphasalazine produced a non significant, but quite consistent, reduction in LTB4 release (-37%). The release of 5-ASA after sulphasalazine was higher in the small intestine, lower in the colon compared to that following 5-ASA-glutamate administration. CONCLUSIONS: 5ASA-glutamate was effective in reducing the macroscopic and histologic score in the trinitrobenzensulfonic acid induced colitis. It also had some effect in reducing eicosanoid synthesis and could be a promising drug for the treatment of inflammatory bowel disease.

Animals↗
PubMed1997

Polycythemia vera treated with recombinant interferon-alpha 2a: evidence of a selective effect on the malignant clone.

We periodically analyzed bone-marrow cytogenetic features in 8 patients belonging to a series of 38 subjects with polycythemia vera (PV), all treated with recombinant interferon-alpha 2a (rIFN-alpha) at a weekly dose of 9,000,000 IU. Six out of these 8 patients never showed any chromosome alterations, while 2 displayed at diagnosis the presence of trisomy 8 in all bone-marrow metaphases. Interestingly enough, in these 2 patients rIFN-alpha treatment was able to induce not only complete hematological response but also the disappearance of trisomy 8, as shown by conventional cytogenetic investigation and fluorescence in situ hybridization performed on bone-marrow cells after 1 year of treatment. This finding indicates that, as previously shown in chronic myeloid leukemia, in PV rIFN-alpha can also eradicate the malignant clone by means of a selective effect on bone-marrow transformed cells.

Adult↗
PubMed1997

Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei.

BACKGROUND & AIMS: Bile acids exert cellular and molecular effects in the liver, but little is known about tissue concentrations. The aim of this study was to characterize bile acid composition in human and rat liver tissue and hepatocyte nuclei and examine the effects of experimental cholestasis and bile acid administration. METHODS: Bile acids were measured by gas chromatography-mass spectrometry. RESULTS: Liver tissue concentrations of sham-operated rats were 130.8 +/- 21.3 nmol/g, representing 2%-4% of the bile acid pool; cholic and delta 22-beta-muricholic acids were the major bile acids identified. Concentrations increased 7-8-fold with bile duct ligation; deoxycholate and hyodeoxycholate disappeared. Lithocholate concentrations were higher in ligated rats (6.4 +/- 0.4 vs. 3.9 +/- 0.5 nmol/g for sham-operated). Total bile acid concentrations in human liver tissue were 61.6 +/- 29.7 nmol/g and comprised mainly chenodeoxycholic and cholic acids. Concentrations were higher during ursodeoxycholate or tauroursodeoxycholate administration (157.2 +/- 45.6 and 161.6 +/- 43.4 nmol/g, respectively), and liver tissue was enriched 30% in ursodeoxycholate at the expense of hydrophobic bile acids. Bile acids were identified in rat hepatic nuclei (50-110 pmol/4 x 10(7) nuclei), accounting for < 0.1% of liver tissue levels. CONCLUSIONS: Human and rat liver tissue bile acid concentrations are low, increase with bile acid administration or bile duct ligation, and account for only a small fraction of the bile acid pool.

Adult↗
PubMed1997

A possible role for the cortisol/anticortisols imbalance in the progression of human immunodeficiency virus.

The progression of HIV infection is accompanied by complex alterations in the production of adrenal steroids. Cortisol levels are increased in HIV infection whereas those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. The progression of HIV infection to AIDS is also characterised by a shift from a type 1 to type 2 cytokine production. Thus, defective production of interferon gamma (IFN gamma), interleukin (IL)-2, and IL-12 as well as increased production of IL-4, IL-5, IL-6, and IL-10 are observed in HIV-seropositive individuals and are proposed to be in vitro immunologic marker of progression. Cortisol and pharmacological doses of glucocorticoids (GC) suppress IL-2 and IFN gamma production and favour the production of IL-4. Furthermore, GC and IL-4 stimulate the differentiation of B lymphocytes into IgE producing plasma cells, the concentration of which augments in HIV infection. Finally, GC induce programmed cell death (PCD) in a variety of different cells, including mature T lymphocytes, and type 2 cytokines were recently proposed to augment the susceptibility of T lymphocytes to PCD. It was suggested that the progressive shift from type 1 to type 2 cytokine production characteristic of HIV infection could be at least partially provoked by the increase in the production of cortisol and the reduction of DHEA. This hypothesis is discussed within the scenario of an endrocrinologic imbalance being responsible for HIV progression at least partially via increased susceptibility of HIV + CD4 lymphocyte to PCD.

Disease Progression↗
PubMed1997

Local and systemic effects of intraduodenal exposure to topical gallstone solvents ethyl propionate and methyl tert-butyl ether in the rabbit.

During topical dissolution of gallstones, solvent can escape to the duodenum causing toxic effects that have not yet been adequately quantified. We compared the local intestinal cytotoxic and systemic hepatotoxic effects of two gallstone solvents, methyl tert-butyl ether and ethyl propionate, on the rabbit's duodenum. Methyl tert-butyl ether, ethyl propionate, or saline (control) was infused intraduodenally for 3 hr in 32 male New Zealand rabbits. The solvents were infused either at a high infusion rate of 8.5 microl/min or at a low rate of 4.0 microl/min. Blood samples were collected for biochemical analysis from each animal before and after the 3-hr infusion period. A standardized histologic scoring system was used by a pathologist blinded to the treatments to quantify liver and intestinal tissue injury. None of the animals studied showed any significant changes in serum alkaline phosphatase, amylase, bilirubin, or their hepatic histology or histologic scoring for mucosal necrosis and ulceration. At the higher dose, methyl tert-butyl ether produced significantly more submucosal inflammation (P = 0.0017) and showed a trend of causing more submucosal edema than ethyl propionate, but ethyl propionate led to significantly higher elevations of aminotransferases than methyl tert-butyl ether as compared to saline. There were no detectable blood levels of methanol or ethanol in any of the animals studied. Ethyl propionate may be less damaging to the intestinal mucosa of the rabbit than methyl tert-butyl ether, but at the higher dose (equivalent to 60 ml/3 hr in a 70-kg human) it appears to produce more biochemical liver injury when administered intraduodenally.

Administration, Topical↗
PubMed1997

Alveolar epithelial cells in vitro produce gelatinases and tissue inhibitor of matrix metalloproteinase-2.

Type II pneumocytes are key cells of the alveolar epithelium. They lie on the alveolar basement membrane, which influences their phenotype and functions. We hypothesized that type II pneumocytes degrade basement membrane components by producing gelatinases, members of the matrix metalloproteinase family. To investigate this hypothesis, we used primary cultures of rat type II pneumocytes and cultures of the human A549 cell line. We found by zymography that 70-kDa gelatinase was present in media conditioned by these cells. This 70-kDa gelatinase was identified as gelatinase A by a Western blot, and the presence of its mRNA was demonstrated by reverse transcription-polymerase chain reaction. A 95-kDa gelatinase could be induced under certain conditions. Production of gelatinases may take place during the turnover of basement membranes, in physiological and in pathophysiological processes. This was suggested by the increase in production of both gelatinases that we observed after in vitro exposure to LPS or interleukin-1. The presence of tissue inhibitors of matrix metalloproteinase-1 and -2 was also demonstrated, suggesting that degradation of extracellular matrix by type II pneumocytes is tightly regulated.

Animals↗
PubMed1997

Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells.

Decrease in alveolar oxygen tension may induce acute lung injury with pulmonary edema. We investigated whether, in alveolar epithelial cells, expression and activity of epithelial sodium (Na) channels and Na,K-adenosine triphosphatase, the major components of transepithelial Na transport, were regulated by hypoxia. Exposure of cultured rat alveolar cells to 3% and 0% O2 for 18 h reduced Na channel activity estimated by amiloride-sensitive 22Na influx by 32% and 67%, respectively, whereas 5% O2 was without effect. The decrease in Na channel activity induced by 0% O2 was time-dependent, significant at 3 h of exposure and maximal at 12 and 18 h. It was associated with a time-dependent decline in the amount of mRNAs encoding the alpha-, beta-, and gamma-subunits of the rat epithelial Na channel (rENaC) and with a 42% decrease in alpha-rENaC protein synthesis as evaluated by immunoprecipitation after 18 h of exposure. The 0% O2 hypoxia also caused a time-dependent decrease in (1) ouabain-sensitive 86Rubidium influx in intact cells, (2) the maximal velocity of Na,K-ATPase on crude homogenates, and (3) alpha1- and beta1-Na,K-ATPase mRNA levels. Levels of rENaC and alpha1-Na,K-ATPase mRNA returned to control values within 48 h of reoxygenation, and this was associated with complete functional recovery. We conclude that hypoxia induced a downregulation of expression and activity of epithelial Na channels and Na,K-ATPase in alveolar cells. Subsequent decrease in Na reabsorption by alveolar epithelium could participate in the maintenance of hypoxia-induced alveolar edema.

Animals↗