Polyamine synthesis in rat lungs injured with alpha-naphthylthiourea

The diamine, putrescine, and polyamines, spermidine and spermine, are low molecular weight organic cations with documented regulatory roles in cell growth and differentiation. Multiple lines of direct and indirect evidence suggest that these organic cations also may function in stimulus-response coupling processes regulating cellular injury and repair. For example, recent studies in monocrotaline-treated rats, hyperoxic rats, and in cultured pulmonary endothelial cells suggest that polyamines regulate pulmonary endothelial integrity and may thus participate in development and/or regression of acute edematous lung injury. To determine if the polyamines are involved in a well-characterized animal model of acute lung injury, the present experiments assessed the relation between changes in polyamine synthesis and development of edema in lungs from rats treated with alpha-naphthylthiourea (ANTU). ANTU caused dose- and time-dependent increases in the lung activity of the initial and rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) and in the lung contents of the polyamines putrescine, spermidine, and spermine. ANTU also caused dose- and time-dependent increases in the lung wet-to-dry weight ratio indicative of pulmonary edema formation. Changes in lung polyamine biosyntheic activity after ANTU did not relate temporally to changes in the lung wet-to-dry weight ratio: ODC activity was depressed during the 3-h period immediately following ANTU administration, a period when the wet-to-dry weight ratio was increasing, and markedly elevated at 18 h after ANTU administration when the wet-to-dry weight ratio had returned to control levels. Pretreatment of the animals with alpha-difluoromethylornithine, a highly specific inhibitor of ODC, failed to attenuate ANTU-induced increases in lung wet-to-dry weight ratio. These observations indicate polyamine synthesis is enhanced in rat lungs with ANTU-induced pulmonary edema but, unlike certain other models of lung injury and pulmonary edema, accumulation of polyamines probably is not essential for development of edematous lung injury. It is conceivable that in this animal model polyamines play a role in lung repair processes or some longer-term consequence of lung injury.     

Monocrotaline-induced cardiopulmonary injury in rats. Modification by the neutrophil elastase inhibitor SC39026

Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.     

Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat

Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24°C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO-1, MT, NF-κB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-κB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-β and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE.     

Exposure to hypoxia results in uneven pulmonary blood flow distribution prior to pulmonary edema

The effects of hypoxia on pulmonary arterial pressure (PAP) and on development of pulmonary edema, ascertained by changes in lung water and pulmonary vascular permeability were studied in rats using bronchoalveolar lavage (BAL). Rats were exposed to hypobaric hypoxia (P(B) = 290 Torr) for 24 h followed by 4 h of normobaric hypoxia (F(IO)2 0.07) (Hx). Controls were rats maintained in a normoxia (Nx). Mean PAP was 28.3 +/- 0.8 mmHg in Hx, and 18.8 +/- 1.7 mmHg in Nx (mean +/- SD). The wet-to-dry lung weight ratio was significantly higher in Hx. The ratio of fluorescence activity between BAL fluid and plasma 4 h after i.v. injection of FITC-albumin was higher in Hx, suggesting an increased pulmonary microvascular permeability in Hx. In a separate study, pulmonary blood flow distribution, measured after 10 min of hypoxia (F(IO)2 0.07) using non-radioactive microspheres, was significantly more heterogeneous than Nx, suggesting a non-homogeneous hypoxic pulmonary vasoconstriction. The combined data of both studies suggest that hypoxia induces heterogeneous pulmonary blood flow distribution which is followed by increased vascular permeability and the development of pulmonary edema.     

Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx

Acute respiratory distress syndrome (ARDS) is a devastating disorder that is characterized by increased vascular endothelial permeability and inflammation. Unfortunately, no effective treatment beyond supportive care is available for ARDS. Astilbin, a flavonoid compound isolated from Rhizoma Smilacis Glabrae, has been used for anti-hepatic, anti-arthritic, and anti-renal injury treatments. This study examined the effects of Astilbin on pulmonary inflammatory activation and endothelial cell barrier dysfunction caused by Gram-negative bacterial endotoxin lipopolysaccharide (LPS). Endothelial cells from human umbilical veins or male Kunming mice were pretreated with Astilbin 24 h before LPS stimulation. Results showed that Astilbin significantly attenuated the pulmonary histopathological changes and neutrophil infiltration 6 h after the LPS challenge. Astilbin suppressed the activities of myeloperoxidase and malondialdehyde, as well as the expression of tumor necrosis factor-α and interleukin-6 in vivo and in vitro. As indices of pulmonary edema, lung wet-to-dry weight ratios, were markedly decreased by Astilbin pretreatment. Western blot analysis also showed that Astilbin inhibited LPS-induced activation of mitogen-activated protein kinase (MAPK) pathways in lung tissues. Furthermore, Astilbin significantly inhibited the activity of heparanase and reduced the production of heparan sulfate in the blood serum as determined by ELISA. These findings indicated that Astilbin can alleviate LPS-induced ARDS, which potentially contributed to the suppression of MAPK pathway activation and the degradation of endothelial glycocalyx.     

Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats

The effects of carbazochrome sodium sulfonate (AC-17), a capillary stabilizer, on pulmonary edema and dysfunction induced by ioxaglate, an ionic radiographic contrast medium, were evaluated in rats. The pulmonary edema was evaluated by the extravasation of intravenously injected Evans blue into lung tissues, while pulmonary dysfunction was determined by monitoring blood gasses including pO(2). Ioxaglate (4 g I/kg, i.v.) caused a marked increase in vascular permeability and a decrease in arterial pO(2). AC-17 reversed the ioxaglate-induced vascular hyperpermeability in a dose-dependent manner. In addition, AC-17 (10 mg/kg) significantly inhibited the decrease in arterial pO(2). In isolated rat pulmonary mast cells, ioxaglate markedly enhanced the histamine release, which was not affected by AC-17. On the other hand, AC-17 did significantly blocked the hyperpermeability induced in cultured bovine endothelial cells by tryptase, thrombin and proteinase-activated receptor-2 agonist peptide (SLIGKV-NH(2)). These findings suggest that AC-17 blocks radiographic contrast medium-induced pulmonary dysfunction by maintaining the endothelial barrier function. Thus, the compound is potentially useful for the prophylaxis of contrast media-induced acute pulmonary adverse events during angiography.     

Decrease in the Ca2+-activated K+ current of pulmonary arterial smooth muscle in pulmonary hypertension rats

Pulmonary hypertension exhibits acute elevation of vascular tone and hyperreactivity of pulmonary vasculature, which are closely related to patient mortality. In the present study, we investigated the characteristics of membrane currents of isolated pulmonary artery smooth muscle cells taken from rats with monocrotaline-induced pulmonary hypertension. Male Wistar rats were given a single subcutaneous injection of monocrotaline or saline, and then sacrificed between 18 to 21 days after the injection. The membrane currents in the smooth muscle cells from both groups of rats were compared using the whole-cell patch clamp technique. With 0.1 mM EGTA in the pipette, the densities of outward currents in monocrotaline-injected rats were smaller than those in control rats. When EGTA in patch pipettes was increased to 10 mM, the densities of the outward currents in monocrotaline-injected rats were equal to those of control rats. The Ca2+-activated K+ channel blockers (TEA, iberiotoxin) and nisoldipine were less effective on the outward currents of monocrotaline-injected rats. In the current clamp mode, a depolarization of membrane potential induced by 4-aminopyridine was greater in monocrotaline-injected rats than in control rats because of the reduced activity of the Ca2+-activated K+ channels. The Ca2+-activated K+ channels were decreased in pulmonary hypertension. The reduced activity of the currents may be related to the vascular hyperreactivity in pulmonary hypertension.     

白藜芦醇对脂多糖诱导小鼠急性肺损伤的保护作用

目的研究白藜芦醇对脂多糖(LPS)致小鼠急性肺损伤(ALI)的保护作用,探讨其可能的作用机制。方法以小鼠气道滴注LPS制备急性肺损伤模型,检测气道吸气阻力(Ri)、气道呼气阻力(Re)和动态肺顺应性(Cdyn)的变化,测定支气管肺泡灌洗液(BALF)中白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的含量,检测肺湿/干比值和毛细血管通透性,观察组织病理学变化。结果白藜芦醇能明显抑制Ri、Re增长和Cdyn降低,降低BALF中IL-1βI、L-6、TNF-α的含量,降低肺湿/干比值和渗透性,减轻肺组织病理学的损伤。结论白藜芦醇对LPS诱导的ALI具有保护作用,作用机制可能与抑制炎症因子的合成与释放有关。     

Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: role of adenosine receptors

Recent studies have been focused on the protective role of ischemic preconditioning against ischemia-reperfusion injury of the lung occurring following cardiopulmonary by-pass surgery and lung or heart transplantation. The present study was undertaken to investigate the role of adenosine in ischemic preconditioning in the isolated buffer-perfused rat lung. Since the pulmonary perfusion flow rate and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. When compared to control values, ischemia-reperfusion injury in the form of 2 h of normothermic ischemia significantly reduced the pulmonary vasoconstrictor response to phenylephrine and KCl, increased wet-to-dry lung weight ratios and increased malondialdehyde content of rat lungs. Ischemic preconditioning in the form of one cycle of 5 min of ischemia and reperfusion applied prior to ischemia-reperfusion, as well as, adenosine preconditioning in the form of adenosine infusion prior to ischemia-reperfusion independently prevented the reduction in pulmonary vasoconstrictor responses and the increases in pulmonary edema and malondialdehyde formation in response to ischemia-reperfusion injury. Pretreatment with adenosine receptor antagonists, theophylline or 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX) prior to ischemic preconditioning or adenosine preconditioning abolished the protective effects of preconditioning by ischemic preconditioning and adenosine preconditioning. The present data demonstrate that ischemic preconditioning and adenosine preconditioning prevent the vascular and biochemical alterations studied in response to ischemia-reperfusion injury in the pulmonary vascular bed of the rat. Results of the present study suggest activation of adenosine A(1) receptors mediates the protective properties of ischemic preconditioning and adenosine preconditioning on ischemia-reperfusion injury in the lung. Moreover, the present data further suggest selective adenosine receptor agonists may be useful as pharmacologic preconditioning agents in preventing ischemia-reperfusion injury in lung transplantation and other forms of pulmonary vascular ischemia.     

Interleukin-1 induced vascular pathology "in vivo": a scanning electron-microscopy study

Ethylene vinyl acetate (EVA) discs containing either 50 U interleukin-1 (IL-1) or 250 mg bovine serum albumin as control were implanted around the exposed jugular veins of rabbits. After 24 hr, the veins were examined by scanning electron-microscopy. Compared with minor changes in control vein lumena, those of EVA-IL-1 treated veins showed extensive endothelial cell denudation and exposure of basement membrane associated with platelet accumulation and adherence/subendothelial migration of leucocytes. These observations suggest that locally-released IL-1 provokes significant vascular pathological changes "in vivo" and emphasise the importance of this cytokine as a mediator of inflammatory and thrombotic/atherosclerotic diseases.     

Suppression of polyamine biosynthesis prevents monocrotaline-induced pulmonary edema and arterial medial thickening

Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.     

Effect of nitrite on endothelial function in isolated lung

Nitrated tyrosine, implicated in protein dysfunction, is increased in various tissues in association with diverse pathological processes. Angiotensin converting enzyme (ACE) is a luminal vascular endothelial enzyme whose dysfunction is an early sign of endothelial injury. ACE contains a tyrosine critical for its enzymatic activity. Others have shown that nitrite exacerbates the ACE dysfunction of cultured endothelial cells in contact with activated polymorphonuclear neutrophils (PMN). We hypothesized that exogenous nitrite would enhance endothelial ACE dysfunction associated with PMN activation in the isolated lung. Rats received lipopolysaccharide (LPS) 2 h prior to isolated lung perfusion with Ficoll containing buffer. Either formyl-Met-Leu-Phe (fMLP, 10(-7) M) or phorbol myristate acetate (PMA, 10(-7) M) was used to activate PMN in lungs treated or not treated with 300-microM nitrite. A first pass indicator dilution method and first order reaction kinetics were used to determine ACE activity, while lung Ficoll content served as an index of vascular permeability. Both fMLP and PMA decreased endothelial ACE activity and increased pulmonary artery pressure, edema and vascular permeability. Exogenous nitrate did not potentiate the decrease in ACE activity, the lung injury or nitrotyrosine immunoreactivity of lung homogenates. In contrast to observations in cultured endothelial cells, our findings in the whole lung are compatible with the speculation of others that the rat lung has an unidentified factor, which minimizes accumulation of nitrated proteins.     

Effects of Monocrotaline Pyrrole on Cultured Rat Pulmonary Endothelium

Administration of monocrotaline pyrrole (MCTP), a putative toxic metabolite of the pyrrolizidine alkaloid, monocrotaline (MCT), results in delayed and progressive pneumotoxicity in the rat. It has been suggested that the lung injury caused by this compound may be initiated by an interaction between MCTP and cells of the pulmonary vasculature. A likely site for initial binding of this reactive electrophile is the pulmonary endothelium. MCTP causes direct toxicity to cultured bovine and porcine pulmonary artery endothelial cells (BECs and PECs, respectively), but there exist species differences both in whole-animal response to the parent alkaloid and in cellular response to direct application of MCTP. In this study, the changes in cultured rat pulmonary vascular endothelial cells (RECs) after a single administration of MCTP were characterized in order to compare these with changes previously identified in this species in vivo. Studies with RECs have also provided an additional model for examination of species-related differences in response to this toxicant. MCTP caused a delayed and progressive release of lactate dehydrogenase from REC monolayers. Progressive cell detachment was evident and remaining cells became enlarged, with morphologic changes comparable to those reported previously in BECs, including cytoplasmic vacuolization and nuclear enlargement. MCTP inhibited cell proliferation at concentrations of 0.05 μg MCTP/ml or greater, and DNA crosslinking was evident at 24 and 48 hr post-treatment. These results suggest that MCTP is directly toxic to cultured RECs, and the development of changes is reminiscent of that seen in the rat in vivo. The cytostatic nature of the compound, in combination with its cytolytic effect on RECs, could contribute to the development of pulmonary edema and other lung vascular changes seen in rats treated with MCT or MCTP.     

Rho-kinase as a potential therapeutic target for the treatment of pulmonary hypertension

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by vasoconstriction and vascular remodeling. Recently, rapidly increasing evidence from various rat models of PH and patients with PH suggest that small GTPase Rho and its downstream effector, Rho-kinase, play a key role in the pathogenesis of PH. Activation of the Rho/Rho-kinase pathway is important for pulmonary endothelial dysfunction, pulmonary vascular smooth muscle cell contractility, proliferation and apoptosis in PH. A greater Rho-kinase expression and an enhanced Rho-kinase activity have been observed in pulmonary arteries of PH rats, such as hypoxia-induced, monocrotaline-induced and genetic spontaneous PH rats. Moreover, Y-27632 or fasudil, the selective Rho-kinase inhibitors, significantly attenuated PH in various pulmonary hypertensive model rats and patients with PH, but did not reduce systemic blood pressure. Therefore, Rho-kinase inhibitors may have therapeutic potential for the treatment of PH.     

Stabilization of ornithine decarboxylase in mouse liver and lung by methylglyoxal bis(cyclohexylamidinohydrazone)

The intraperitoneal injection of methylglyoxal bis(cyclohexylamidinohydrazone) (MGBC), an inhibitor of S-adenosylmethionine decarboxylase and spermidine synthase, markedly increased (7-fold of the basal level at 4 hr) ornithine decarboxylase (ODC) activity in normal mouse liver. ODC activity was also increased 2.5-fold over the basal level in mouse lung at 6 hr after the injection. The effect of MGBC on ODC activity occurred in a dose-dependent manner. Measurement of the apparent half-life of ODC induced in the liver and lung by MGBC treatment revealed a clear decrease in the decay rate of the enzyme in both the tissues. Activities of S-adenosylmethionine decarboxylase (AdoMetDC) and spermidine/spermine N1-acetyltransferase (SAT) were not increased by the intraperitoneal injection of MGBC. There was a large rise in putrescine and a fall in spermidine and spermine in the liver and lung except for brain within an 8 hr period in response to MGBC, suggesting that these changes resulted from the stabilization of ODC and inhibitions of AdoMetDC and spermidine synthase.     

Effect of multi-walled carbon nanotube surface modification on bioactivity in the C57BL/6 mouse model

The current study tests the hypothesis that multi-walled carbon nanotubes (MWCNT) with different surface chemistries exhibit different bioactivity profiles in vivo. In addition, the study examined the potential contribution of the NLRP3 inflammasome in MWCNT-induced lung pathology. Unmodified (BMWCNT) and MWCNT that were surface functionalised with -COOH (FMWCNT), were instilled into C57BL/6 mice. The mice were then examined for biomarkers of inflammation and injury, as well as examined histologically for development of pulmonary disease as a function of dose and time. Biomarkers for pulmonary inflammation included cytokines, mediators and the presence of inflammatory cells (IL-1β, IL-18, IL-33, cathepsin B and neutrophils) and markers of injury (albumin and lactate dehydrogenase). The results show that surface modification by the addition of the -COOH group to the MWCNT, significantly reduced the bioactivity and pathogenicity. The results of this study also suggest that in vivo pathogenicity of the BMWCNT and FMWCNT correlates with activation of the NLRP3 inflammasome in the lung.     

Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

Chlorine is a highly toxic respiratory irritant that when inhaled causes epithelial cell injury, alveolar-capillary barrier disruption, airway hyperreactivity, inflammation, and pulmonary edema. Chlorine is considered a chemical threat agent, and its release through accidental or intentional means has the potential to result in mass casualties from acute lung injury. The type 4 phosphodiesterase inhibitor rolipram was investigated as a rescue treatment for chlorine-induced lung injury. Rolipram inhibits degradation of the intracellular signaling molecule cyclic AMP. Potential beneficial effects of increased cyclic AMP levels include inhibition of pulmonary edema, inflammation, and airway hyperreactivity. Mice were exposed to chlorine (whole body exposure, 228-270 ppm for 1 h) and were treated with rolipram by intraperitoneal, intranasal, or intramuscular (either aqueous or nanoemulsion formulation) delivery starting 1 h after exposure. Rolipram administered intraperitoneally or intranasally inhibited chlorine-induced pulmonary edema. Minor or no effects were observed on lavage fluid IgM (indicative of plasma protein leakage), KC (Cxcl1, neutrophil chemoattractant), and neutrophils. All routes of administration inhibited chlorine-induced airway hyperreactivity assessed 1 day after exposure. The results of the study suggest that rolipram may be an effective rescue treatment for chlorine-induced lung injury and that both systemic and targeted administration to the respiratory tract were effective routes of delivery.     

Acute Effects of Endotoxin Inhalation on the Respiratory Tract in Pigs: Interaction with Ammonia

Abstract

The acute respiratory effects of endotoxin inhalation (0–400 μ/kg) have been evaluated in pigs. Endotoxin (LPS from Escherichia coli 0127:B8 and 055:B5) nebulization had no direct effect on the nasal mucosa. An in vitro bronchial hyperreactivity to acetylcholine and histamine, related to the endotoxin dosage, was recorded. In the lung, significant endotoxin dose-dependent increases in the total cell, alveolar macrophage, and neutrophil counts in the BAL fluid were recorded. Following intrabronchial administration of endotoxin, the cellular response was significantly higher than that obtained after nebulization. Neither the dry to wet lung weight ratio (DW/WW) nor the albumin concentration in the BAL fluid was affected. When endotoxins were infused intravenously, the lung cellular response was accompanied by an increase in the albumin concentration in the BAL fluid. In pigs exposed for 6 days to 50 ppm ammonia, endotoxin nebulization induced a significant increase in the albumin concentration and tented to increase the number of neutrophils in the NAL fluid. Ammonia did not alter the lung response to endotoxin inhalation. It was concluded that endotoxin nebulization can produce bronchial hyperreactivity and a cellular inflammatory response in the lung, but without inducing pulmonary edema. Ammonia can interfere with nasal response to endotoxins. The weak response to endotoxin inhalation could be ascribed to the barrier role played by the alveolar epithelium and to dilution of the aerosol throughout the respiratory system.     

Differential release and effects of LTB4 in guinea-pig lung "in vitro"

LTB4 is a potent chemotactic and chemokinetic eicosanoid released by leukocytes during inflammatory reaction; in addition to this it possesses a bronchopulmonary activity in different animal species. Since cysteinyl containing leukotrienes and other eicosanoids have been shown to induce hyperreactivity of pulmonary smooth muscles, we investigated the release of LTB4 from different anatomical structures of guinea-pig lung in vitro and the possible interaction with histamine in these tissues. In fact, hyperreactivity is evidentiated by a synergism between different mediators. The ovalbumin sensitized guinea-pig lung has been brushed in order to separate lung parenchyma from bronchi and vessels which were divided into large and small preparations. The antigen challenge resulted in a statistically significant increase in LTB4 production in large bronchi and vessels, whereas in the other preparations considered the basal levels of the eicosanoid were not modified during the anaphylactic reaction. In parallel with the differential site of LTB4 release, a positive interaction between LTB4 and histamine was only observed in the pulmonary artery. These data suggest that the possible role of LTB4 in different pulmonary diseases is not confined to the airway smooth muscle but it might be related to its capacity to induce vascular hyperreactivity.     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.