Inflammatory mediators down-regulate 11beta-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and the rat lung

In the lung, anti-inflammatory actions of glucocorticoids would be determined by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the microsomal enzyme responsible for the breakdown of bio-active glucocorticoids. However, regulation of 11beta-HSD2 under inflammatory conditions such as acute lung injury is not well understood. In the present study, we examined whether inflammatory substances would influence the activity and mRNA expression of 11beta-HSD2 in the lung. In a human bronchial epithelial cell line BEAS-2B, endotoxin inhibited 11beta-HSD2 enzyme activity in a dose-dependent manner over 48 h with a significant decrease in the mRNA expression. Likewise, tumor necrosis factor (TNF)-alpha inhibited both activity and mRNA expression of 11beta-HSD2. The TNF-alpha-dependent decrease in the enzyme activity was completely blocked by anti-TNF-alpha antibody, while antibody alone showed no significant influence on the enzyme activity. An nitric oxide donor (NO) sodium nitropusside or a cGMP analog 8-br-cGMP caused moderate but significant decreases in both activity and mRNA expression of 11beta-HSD2. Importantly, treatment of rats with endotoxin significantly decreased both activity and mRNA expression of 11beta-HSD2 in the lung tissue. We conclude that lung inflammation reduces local glucocorticoid breakdown and augments glucocorticoid action in the lung by down-regulating 11beta-HSD2 via multiple mechanisms.     

Adrenalectomy reduces neuropeptide Y-induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus

Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPY-induced food intake was similar in ADX and control rats after acute intracerebroventricular injection of NPY. Injection of NPY caused a significant increase in plasma insulin in control rats, but this effect was completely absent in ADX rats in which basal plasma insulin levels were also lower than controls. In addition, ADX significantly reduced the number of neurons expressing NPY receptor Y(1) and Y(5) mRNAs in the ventromedial hypothalamus (VMH), without affecting Y(1)- or Y(5)-mRNA expression in the paraventricular hypothalamus or the arcuate nucleus. These data indicate that glucocorticoids are necessary for acute NPY-mediated insulin release and suggest that the mechanisms involve glucocorticoid regulation of Y(1) and Y(5) receptors specifically within the VMH nucleus.     

Expression of human group II PLA2 in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate.

Group II PLA2 has been implicated in inflammatory processes in both man and other animals and has been shown to be involved in inflammatory conditions, such as arthritis and sepsis. Transgenic mice expressing the human group II PLA2 gene have been generated using a 6.2-kb genomic fragment. These mice express the group II PLA2 gene abundantly in liver, lung, kidney, and skin, and have serum PLA2 activity levels approximately eightfold higher than nontransgenic littermates. The group II PLA2 transgenic mice reported here exhibit epidermal and adnexal hyperplasia, hyperkeratosis, and almost total alopecia. The chronic epidermal hyperplasia and hyperkeratosis seen in these mice is similar to that seen in a variety of dermatopathies, including psoriasis. However, unlike what is seen with these dermatopathies, no significant inflammatory-cell influx was observed in the skin of these animals, or in any other tissue examined. These mice provide an important tool for examining group II PLA2 expression, and for determining the role of group II PLA2 in normal and disease physiology. They serve as an in vivo model for identifying inhibitors of group II PLA2 activity and gene expression.     

磷脂酶A2在大鼠急性胰腺炎并发肺损伤中的作用及维拉帕米的治疗效应

目的：观察磷脂酶A2(PLA2)在大鼠急性胰腺炎(AP)并发肺损伤中的作用及维拉帕米(verapamil)的治疗效应，并对其治疗作用的机制进行探讨。方法：取82只SD大鼠，雌雄不拘，随机数字表法分为模型组、维拉帕米组及假手术组；经胰胆管逆行注射质量分数为3％的牛磺脱氧胆酸钠(0．1ml／100g)，制成AP模型，并按分组情况分别给予药物或生理盐水；制模后4h、8h记录腹水量，测定血浆中钙离子浓度和淀粉酶活性及腹水和肺组织匀浆中PLA2活性的变化，计算肺系数，光镜下观察胰腺及肺组织的病理变化，记录动物的存活时间及24h死亡率。结果：维拉帕米能有效减轻AP大鼠胰腺及肺组织的病理性损伤，减少腹水生成；与模型组相比，维拉帕米组血浆钙离子浓度进行性下降的程度减轻，淀粉酶活性降低，腹水及肺匀浆中PLA2活性显著降低；维拉帕米可降低AP大鼠的死亡率，延长动物的生存时间。结论：PLA2在AP并发肺损伤的病理过程中发挥重要的作用，维拉帕米可以通过钙通道拮抗作用抑制PLA2的活性，减轻胰腺及肺的损伤而对AP并发肺损伤发挥治疗作用。     

The potent anti-Staphylococcus aureus activity of a sterile rabbit inflammatory fluid is due to a 14-kD phospholipase A2.

The cell-free fluid (ascitic fluid, AF) of a sterile inflammatory peritoneal exudate elicited in rabbits is potently bactericidal for complement-resistant gram-negative as well as gram-positive bacterial species. This activity is absent in plasma. We now show that essentially all activity in AF against Staphylococcus aureus is attributable to a group II 14-kD phospholipase A2 (PLA2), previously purified from AF in this laboratory. Antistaphylococcal activity of purified PLA2 and of whole AF containing a corresponding amount of PLA2 was comparable and blocked by anti-AF-PLA2 serum. At concentrations present in AF (approximately 10 nM), AF PLA2 kills > 2 logs of 10(6) S. aureus/ml, including methicillin-resistant clinical isolates, and other species of gram-positive bacteria. Human group II PLA2 displays similar bactericidal activity toward S. aureus (LD90 approximately 1-5 nM), whereas 14-kD PLA2 from pig pancreas and snake venom are inactive even at micromolar doses. Bacterial killing by PLA2 requires Ca2+ and catalytic activity and is accompanied by bacterial phospholipolysis and disruption of the bacterial cell membrane and cell wall. These findings reveal that group II extracellular PLA2, the function of which at inflammatory sites has been unclear, is an extraordinarily potent endogenous antibiotic against S. aureus and other gram-positive bacteria.     

Adrenal gland-dependent augmentation of plasminogen activator inhibitor-1 expression in streptozotocin-induced diabetic mice

BACKGROUND: Diabetes is associated with an excess risk of cardiac events, and one risk factor for infarction is an elevated level of plasminogen activator inhibitor-1 (PAI-1). OBJECTIVES AND METHODS: To evaluate whether the glucocorticoid hormones are involved in the diabetes-induced PAI-1 production, we examined expression profiles of PAI-1 mRNA in adrenalectomized (ADX) mice with streptozotocin (STZ)-induced diabetes. RESULTS: The diabetes-induced augmentation of plasma PAI-1 levels and PAI-1 mRNA expression in the heart and lungs was completely normalized in diabetic ADX mice. The glucocorticoid receptor antagonist RU486 significantly, but only partly suppressed PAI-1 induction in STZ-induced diabetic mice, suggesting that factors other than glucocorticoids are also involved in PAI-1 induction provoked by diabetes. CONCLUSION: Our results suggested that the adrenal gland plays a critical role in the progression of thrombosis in diabetic patients by inducing expression of the PAI-1 gene.     

Cytokine-stimulated secretion of group II phospholipase A2 by rat mesangial cells. Its contribution to arachidonic acid release and prostaglandin synthesis by cultured rat glomerular cells.

Potent pro-inflammatory cytokines, such as interleukin 1 (IL-1) or tumor necrosis factor (TNF) alpha have been found to increase group II phospholipase A2 (PLA2) synthesis and secretion by mesangial cells. In all cases 85-90% of the enzyme is secreted from the cells and a parallel increase in prostaglandin (PG)E2 synthesis is observed. We report here that co-incubation with a monoclonal antibody that specifically binds and neutralizes rat group II PLA2 attenuates IL-1 beta and TNF alpha-stimulated PGE2 production by 45% and 52%, respectively. CGP43182, a specific inhibitor of group II PLA2, potently blocks mesangial cell group II PLA2 in vitro with a half-maximal inhibitory concentration (IC50) of 1.5 microM, while only slightly affecting mesangial cell high molecular weight PLA2. CGP 43182 markedly attenuates IL-1 beta- and TNF alpha-stimulated PGE2 synthesis in intact mesangial cells with IC50's of 1.3 and 1.0 microM, respectively. PLA2 secreted from cytokine-stimulated mesangial cells was purified to homogeneity. Addition of the purified enzyme to unstimulated mesangial cells causes a marked release of arachidonic acid and a subsequent increased synthesis of PGE2. Moreover, addition of purified PLA2 to a cloned rat glomerular epithelial cell line and cultured bovine glomerular endothelial cells augmented both arachidonic acid release and PGE2 synthesis, with the endothelial cells being especially sensitive. Thus, cytokine-triggered synthesis and secretion of group II PLA2 by mesangial cells contributes, at least in part, to the observed synthesis of PGE2 that occurs in parallel to the enzyme secretion. Furthermore, extracellular PLA2 secreted by mesangial cells is able to stimulate arachidonic acid release and PGE2 synthesis by the adjacent endothelial and epithelial cells. These data suggest that expression and secretion of group II PLA2 triggered by pro-inflammatory cytokines may crucially participate in the pathogenesis of inflammatory processes within the glomerulus.     

Inhibition of glucocorticoid receptor binding by nitric oxide in endotoxemic rats

OBJECTIVE: Nitric oxide is an important participant in septic shock. For example, it causes profound vasodilation and hypotension. Despite their potent antiinflammatory properties, glucocorticoids are not routinely used in septic shock. Some studies show that antiinflammatory doses of glucocorticoids can be beneficial, but other studies do not indicate their use in this situation. We have previously shown the inhibitory effect of nitric oxide on glucocorticoid receptor binding in vitro. Nitric oxide donors decreased the binding of immunoprecipitated glucocorticoid receptor obtained from mouse L929 fibroblasts. These in vitro findings prompted us to study whether in vivo manipulations of the nitric oxide system would interfere with the glucocorticoid receptor binding. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university. SUBJECTS: Female Wistar rats. INTERVENTIONS: Injection of bacterial lipopolysaccharide, anesthesia, cardiovascular perfusion, and organ removal for biochemical assays. MEASUREMENTS AND MAIN RESULTS: Following lipopolysaccharide injection, plasma nitrate + nitrite increased and inducible nitric oxide synthase activity was stimulated in several organs, the highest rates being in the lung and spleen. If dexamethasone was injected before lipopolysaccharide, it completely blocked inducible nitric oxide synthase induction and the increase in plasma nitrate + nitrite. On the other hand, if dexamethasone was injected after lipopolysaccharide, it failed to affect both inducible nitric oxide synthase induction and increased plasma nitrate + nitrite levels. Lipopolysaccharide also caused an inhibition of glucocorticoid receptor binding in lung and spleen. Previous administration of a nitric oxide synthase inhibitor prevented both lipopolysaccharide-induced decrease in glucocorticoid receptor binding and the increase in plasma nitrate + nitrite. Injection of a nitric oxide donor into naive animals significantly decreased glucocorticoid receptor binding activity and prevented dexamethasone-induced increase in liver tyrosine aminotransferase activity. CONCLUSIONS: The results indicate that the failure of glucocorticoids to exhibit their antiinflammatory effects when administered to endotoxemic rats may be explained, at least in part, by the nitric oxide-induced inhibition of glucocorticoid receptor binding ability, thus precluding the expression of the antiinflammatory effects of both exogenous and endogenous corticosteroids.     

胰岛素样生长因子结合蛋白-2与足月及早产新生大鼠高氧肺损伤的关系

目的 探讨高浓度氧对足月及早产新生大鼠肺发育的影响及高氧肺损伤与胰岛素样生长因子结合蛋白-2(IGFBP-2)的关系.方法 将孕22 d自然出生(足月)及孕21 d行剖宫术提前娩出(早产)的新生大鼠在生后2 d随机分为足月空气组(I组)、足月高氧组(Ⅱ组)、早产空气组(Ⅲ组)、早产高氧组(Ⅳ组).Ⅱ、Ⅳ组持续暴露于氧含量为85%的氧箱中,I、Ⅲ组置于同室空气中.每日记录大鼠存活率,分别于出生后4、7、10、14和21 d活杀取肺组织标本,作病理学检查、辐射状肺泡计数(RAC).用蛋白质免疫印迹法(Western blotting)及逆转录-聚合酶链反应(RT-PCR)分别测定IGFBP-2肺表达浓度及mRNA表达.结果 高氧组自出生7 d后大鼠存活率较空气组显著下降(P均0.05).空气组肺组织无炎症病变;高氧组出生7 d和14 d时呈肺泡炎改变,21 d时肺泡炎改变明显加重,且肺泡生成受阻滞,肺泡结构囊泡化;Ⅱ、Ⅳ组各时间点RAC值较相应I、Ⅲ组显著减少(P均<0.01).高氧Ⅱ、Ⅳ组出生4 d和14 d IGFBP-2表达强度均较对应的I、Ⅲ组增强(P均<0.01);IGFBP-2 mRNA表达变化与其肽浓度变化相似.结论 长期高氧暴露可引起足月和早产新生大鼠亚急性肺损伤和肺发育阻滞,IGFBP-2异常表达;这可能是高氧导致亚急性肺损伤及肺发育阻滞的重要机制之一.     

支气管肺泡灌洗对肠源性感染致早期肺损伤的诊断价值

目的　观察肠源性感染致肺损伤时炎症介质的变化 ,探讨支气管肺泡灌洗对早期肺损伤的诊断价值。方法　采用大鼠盲肠结扎并穿孔造成腹腔感染制备肠源性感染动物模型 ,并设假手术对照组。分别在术后 0、2 4、4 8、72、96和 12 0 h处死一组大鼠 ,取支气管肺泡灌洗液 (BAL F)进行细胞学分析 ,检测 BAL F、肺组织和血浆的内毒素、磷脂酶 A2 (PL A2 )和肿瘤坏死因子 α(TNFα)含量。结果　 BAL F的中性粒细胞百分率逐渐增加 ,时间越长越明显。BAL F、肺组织和血浆的内毒素、PL A2 逐渐增加 ,三者之间两两相关 (BAL F与肺 :r=0 .90 4 ,P<0 .0 5 ;BAL F与血浆 :r=0 .895 ,P<0 .0 5 ;肺与血浆 :r=0 .94 6 ,P<0 .0 1) ;TNFα也随时间的延长而逐渐增加 ,BAL F和肺组织的 TNFα显著相关 (r=0 .95 2 ,P<0 .0 1) ,两者与血浆的 TNFα无明显相关性 (r1 =0 .6 84 ,r2 =0 .6 0 8,P均 >0 .0 5 )。结论　支气管肺泡灌洗可发现早期的肠源性肺损伤。     

Induction by Glucocorticoids of Angiotensin Converting Enzyme Production from Bovine Endothelial Cells in Culture and Rat Lung In Vivo

The effect of corticosteroids on angiotensin converting enzyme was investigated in endothelial cell cultures and intact rat lung. Cultured endothelial cells from bovine aorta showed net production of angiotensin converting enzyme (ACE) over 2 d culture in serum-free medium. Dexamethasone (DM) increased cell ACE activity six- to sevenfold at 100 nM with a threshold effect at 0.3 nM. The effect of DM on ACE production was completely inhibited by actinomycin D or cycloheximide. Deoxycorticosterone (DOC) and aldosterone were markedly less active, with a threshold near 100 nM and significant (two to threefold) stimulation of ACE activity at 1 muM. In cells incubated in the presence of 10 nM DM, DOC (10 muM) significantly inhibited ACE production compared with 10 nM DM alone, suggesting that DOC is a partial agonist/partial antagonist in this enzyme system. Protein content of cells or medium was unchanged by steroids at all doses used.In vivo, adrenalectomized rats showed lower pulmonary ACE compared with intact controls, and when injected with DM (40 mug/d for 4 d) showed a significant (twofold, P < 0.002) increase in lung ACE over oil-injected, adrenalectomized controls; serum ACE did not change. Injection with DOC (40 mug/d) or aldosterone (10 mug/d) had no effect on lung or serum ACE. Over a range (0.6 to 2,000 mug) of concentrations of DM administered daily for 7 d, the dose-response curve of DM for induction of pulmonary ACE mirrored that for thymolysis; for both, half-maximal effects were seen at approximately 6 mug DM/d, and plateau levels at 60 mug/d.We conclude that glucocorticoids are potent inducers of ACE activity in endothelial cells in culture and in rat lung in vivo, and that the action of aldosterone and DOC reflects occupancy of glucocorticoid receptors. This effect may be of (patho)physiological relevance in regulating levels of ACE in local vascular beds, and thereby modulating local levels of the vasoactive peptides angiotensin II and bradykinin.     

Interleukin 1 alpha causes rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells.

We have shown previously that interleukin 1 (IL-1) stimulates eicosanoid production in glomerular mesangial cells (MC) by de novo synthesis of a 14-kD, group II phospholipase A2 (PLA2). IL-1-stimulated prostaglandin E2 synthesis precedes expression of this enzyme, suggesting that another PLA2 isoform must be more rapidly activated. In the presence but not absence of calcium inophore, [3H]arachidonate release is increased significantly as early as 5 min after addition of IL-1, and IL-1 concurrently stimulates a Ca(2+)-dependent phospholipase activity, which was characterized as the cytosolic form of PLA2 (cPLA2). IL-1 does not alter either cPLA2 mRNA expression or mass in serum-stimulated MC, suggesting that cPLA2 activity is increased by a posttranslational modification. IL-1 treatment for 30 min doubles 32P incorporation into immunoprecipitable cPLA2 protein, concordant with the increase in enzyme activity. Immunoblot analysis of extracts derived from IL-1-treated (30 min) cells demonstrates a decreased mobility of cPLA2, and treatment of MC lysates with acid phosphatase significantly reduces cytokine-activated cPLA2 activity, further indicating that IL-1 stimulates phosphorylation of the enzyme. IL-1 treatment (24 h) of serum-deprived MC doubled cPLA2 mRNA, protein, and activity. In summary, IL-1 increases cPLA2 activity in a biphasic, time-dependent manner both by posttranslational modification and de novo synthesis. We consider cPLA2 activation a key step in IL-1-stimulated synthesis of pro-inflammatory, lipid mediators, and an integral event in the phenotypic responses induced in target cells by this cytokine.     

Effect of glucocorticoid on MIP-1α and NF-κB expressing in the lung of rats undergoing mechanical ventilation with a high tidal volume

BACKGROUND:

Ventilator induced lung injury (VILI) is a serious complication in the treatment of mechanical ventilating patients, and it is also the main cause that results in exacerbation or death of patients. In this study, we produced VILI models by using glucocorticoid in rats with high tidal volume mechanical ventilation, and observed the content of macrophage inflammatory protein-1α (MIP-1α) in plasma and bronchoalveolar lavage fluid (BALF) and the expression of MIP-1α mRNA and nuclear factor-kappa B (NF-κB) p65 mRNA in the lung so as to explore the role of glucocorticoid in mechanical ventilation.

METHODS:

Thirty-two healthy Wistar rats were randomly divided into a control group, a ventilator induced lung injury (VILI) group, a dexamethasone (DEX) group and a budesonide (BUD) group. The content of MIP-1α in plasma and BALF was measured with ELISA and the level of MIP-1α mRNA and NF-κBp65 mRNA expressing in the lung of rats were detected by RT-PCR. The data were expressed as mean±SD and were compared between the groups.

RESULTS:

The content of MIP-1α in plasma and BALF and the level of MIP-1α mRNA and NF-KBp65 mRNA in the lung in the DEX and BUD groups were significantly lower than those in the VILI group (P<0.001). Although the content of MIP-1α in plasma and BALF and the level of MIP-1α mRNA and NF-κBp65 mRNA in the lung in the BUD group were higher than those in the DEX group, there were no significant differences between them (P>0.05).

CONCLUSIONS:

Glucocorticoid could down-regulate the expression of MIP-1α by inhibiting the activity of NF-κB in the lung and may exert preventive and therapeutic effects on VILI to some extent. The effect of local use of glucocorticoid against VILI is similar to that of systemic use, but there is lesser adverse reaction.KEY WORDS: Mechanical ventilation, Lung injury, Macrophage inflammatory protein-1α, Nuclear factor-kappa B, Glucocorticoid, Inflammation     

Activation of alveolar phospholipase A2 after hydrochloric acid aspiration in rats

PURPOSE: The present study was carried out to determine phospholipase A2 (PLA2) activity in the bronchoalveolar lavage fluid (BALF) in rats subjected to HCI aspiration. MATERIALS AND METHODS: Rats were allocated into one of five groups. Groups H-1 and H-3 received instillation of HCI into lungs. Groups S-1 and S-3 received saline instead of HCI. Group C received no instillation. BAL was performed according to the protocol, that is, 1 hour after the instillation in groups H-1 and S-1, 3 hours after the instillation in groups H-3 and S-3, and arbitrarily in group C. Obtain BALF was analyzed for the protein concentration, PLA2 activity, and the molecular mass of PLA2. RESULTS: The protein concentration in BALF showed an increase in groups H-1 and H-3. PLA2 activity decreased in group H-1, but increased in group H-3, compared with groups S-1 and S-3, respectively. PLA2 in groups C and H-1 revealed a high molecular mass (HM), but that in group H-3 revealed a low molecular mass (LM). CONCLUSIONS: There is an increase in the alveolar LM-PLA2 at inflammatory phase after HCI aspiration, suggesting the pathophysiologic role of LM-PLA2 in the acute lung injury.     

Phospholipases in biology and medicine

Phospholipases, a group of enzymes that catalyze the hydrolysis of membrane phospholipids, are classified according to the bond cleaved in a phospholipid into PLA1 (EC 3.1.1.3), PLA2 (EC 3.1.1.4), PLB (EC 3.1.1.5), PLC (EC 3.1.4.3), and PLD (EC 3.1.4.4). This paper reviews source and structure of PLA2 and the involvement of PLA2 and PLC in several biological phenomena, such as, signal transduction, photoreception, biosynthesis of lung surfactant, sperm motility, and fertilization. New assays for PLA2 activity and concentration in biological fluids are discussed. Phospholipases are involved in many inflammatory reactions by making arachidonate available for eicosanoid biosynthesis. The determination of PLA2 activity and mass concentration in plasma is useful in the diagnosis and prognosis of pancreatitis and of septic shock. Naturally occurring phospholipase inhibitors, such as lipocortins act as second messengers in the anti-inflammatory response to steroids. Lipocortins may be valuable therapeutic agents, because they are more specific in their anti-inflammatory action than glucocorticoids; therefore, they are less likely to produce harmful side effects.     

Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat

OBJECTIVES: 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11beta-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. DESIGN: Controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Adult Sprague-Dawley rats (n = 66). INTERVENTIONS: Rats were intraperitoneally injected with carbenoxolone (2 x 10 mg.kg(-1).day(-1) for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg). MEASUREMENTS AND MAIN RESULTS: We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of alpha-subunit, four-fold increase of beta-subunit, and two-fold increase of gamma-subunit) as well as in trachea. Carbenoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid. CONCLUSIONS: These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.