Plasma Exudation into Airways Induced by Inhaled Platelet-Activating Factor: Effect of Peptidase Inhibition

1991 ◽  
Vol 80 (3) ◽  
pp. 241-247 ◽  
Author(s):  
Jan O. Lötvall ◽  
Wayne Elwood ◽  
Kenichi Tokuyama ◽  
Peter J. Barnes ◽  
K. Fan Chung
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Evans Blue ◽  
Guinea Pigs ◽  
Platelet Activating Factor ◽  
Neutral Endopeptidase ◽  
Blue Dye ◽  
Converting Enzyme ◽  
Evans Blue Dye ◽  
Plasma Exudation ◽  
Lung Resistance

1. To evaluate whether endogenous peptide release is involved in the airway responses to inhaled platelet-activating factor, we measured lung resistance and airway microvascular leakage in anaesthetized guinea pigs pre-treated with inhalation of either saline or a combination of the peptidase inhibitors phosphoramidon (0.1 mmol/l: 60 breaths; 7.5 nmol), to inhibit neutral endopeptidase, and captopril (4.6 mmol/l: 60 breaths; 350 nmol), to inhibit angiotensin-converting enzyme. 2. Airway microvascular leakage was determined by the albumin marker Evans Blue dye injected intravenously (20 mg/kg) before platelet-activating factor or sham challenge. 3. Inhaled platelet-activating factor induced a maximum increase in lung resistance (1.43 ± 0.33 cmH2O s−1 ml−1) which was not significantly different after pretreatment with phosphoramidon and captopril (1.44 ± 0.21 cmH2O s−1 ml−1). 4. Inhalation of platelet-activating factor caused a significant increase in extravasated Evans Blue dye at all airway levels, an effect which was not potentiated by peptidase inhibition. Similar results were obtained with dye extravasated into the airway lumen and absorbed by a filter paper placed on the tracheal mucosa. Approximately 11% of the total tracheal dye was found in the lumen. There was a high correlation between tracheal tissue and tracheal lumen Evans Blue dye (r = 0.91; P < 0.001). 5. We found a significantly lower dry to wet weight ratio in proximal intrapulmonary airways of animals exposed to platelet-activating factor, suggesting that platelet-activating factor caused airway oedema at this airway level. 6. Inhaled platelet-activating factor does not induce immediate release of peptides degraded by either neutral endopeptidase or angiotensin-converting enzyme in high enough quantities to cause bronchoconstriction. Inhaled platelet-activating factor may cause airway narrowing in guinea pigs largely due to plasma exudation into the airway wall and lumen.

Airflow obstruction after substance P aerosol: contribution of airway and pulmonary edema

1990 ◽  
Vol 69 (4) ◽  
pp. 1473-1478 ◽  
Author(s):  
J. O. Lotvall ◽  
R. J. Lemen ◽  
K. P. Hui ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Substance P ◽  
Pulmonary Edema ◽  
Evans Blue ◽  
Guinea Pigs ◽  
Airflow Obstruction ◽  
Maximum Effect ◽  
Blue Dye ◽  
Evans Blue Dye ◽  
Microvascular Leakage ◽  
Lung Resistance

We have studied the effects of aerosolized substance P (SP) in guinea pigs with reference to lung resistance and dynamic compliance changes and their recovery after hyperinflation. In addition, we have examined the concomitant formation of airway microvascular leakage and lung edema. Increasing breaths of SP (1.5 mg/ml, 1.1 mM), methacholine (0.15 mg/ml, 0.76 mM), or 0.9% saline were administered to tracheostomized and mechanically ventilated guinea pigs. Lung resistance (RL) increased dose dependently with a maximum effect of 963 +/- 85% of baseline values (mean +/- SE) after SP (60 breaths) and 1,388 +/- 357% after methacholine (60 breaths). After repeated hyperinflations, methacholine-treated animals returned to baseline, but after SP, mean RL was still raised (292 +/- 37%; P less than 0.005). Airway microvascular leakage, measured by extravasation of Evans Blue dye, occurred in the brain bronchi and intrapulmonary airways after SP but not after methacholine. There was a significant correlation between RL after hyperinflation and Evans Blue dye extravasation in intrapulmonary airways (distal: r = 0.89, P less than 0.005; proximal: r = 0.85, P less than 0.01). Examination of frozen sections for peribronchial and perivascular cuffs of edema and for alveolar flooding showed significant degrees of pulmonary edema for animals treated with SP compared with those treated with methacholine or saline. We conclude that the inability of hyperinflation to fully reverse changes in RL after SP may be due to the formation of both airway and pulmonary edema, which may also contribute to the deterioration in RL.

Role of neutral endopeptidase in bronchial hyperresponsiveness to bradykinin induced by IL-1 beta

1995 ◽  
Vol 78 (3) ◽  
pp. 921-927 ◽  
Author(s):  
H. Tsukagoshi ◽  
J. Sun ◽  
O. Kwon ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Interleukin 1 ◽  
Bronchial Hyperresponsiveness ◽  
Neutral Endopeptidase ◽  
Tracheobronchial Tree ◽  
Blue Dye ◽  
Peptidase Activity ◽  
Converting Enzyme ◽  
Lung Resistance ◽  
Airway Responses

Interleukin-1 beta (IL-1 beta) induces bronchial hyperresponsiveness (BHR) to bradykinin but not to acetylcholine. We examined whether this was mediated through the inhibition of neutral endopeptidase (NEP) activity and/or through the enhancement of airway microvascular leakage (AML) by IL-1 beta. We administered human recombinant IL-1 beta (500 U) or saline intratracheally and 24 h later measured the airway responses to bradykinin (1 mM; 45 breaths). IL-1 beta-treated rats showed a decrease of 18.5 and 21.1% of NEP activity in the lungs and tracheobronchial tree, respectively (P < 0.05), associated with an augmented response in total lung resistance to bradykinin but with no increase in Evans blue dye extravasation used as a marker of AML. Phosphoramidon (0.1 and 1 mM; 90 breaths), an NEP inhibitor, induced a dose-dependent increase in lung resistance to bradykinin without further enhancing BHR induced by IL-1 beta. Bradykinin-induced AML was not enhanced by phosphoramidon in either saline- or IL-1 beta-treated rats. Similarly, after captopril (1 mM; 90 breaths), an inhibitor of angiotensin-converting enzyme, there was no further enhancement of BHR to bradykinin induced by IL-1 beta. BHR to bradykinin induced by IL-1 beta may result from an inhibition of peptidase activity, such as NEP and angiotensin-converting enzyme, and is not associated with an enhancement of AML.

A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig

1992 ◽  
Vol 72 (6) ◽  
pp. 2415-2419 ◽  
Author(s):  
J. Lotvall ◽  
W. Elwood ◽  
K. Tokuyama ◽  
T. Sakamoto ◽  
P. J. Barnes ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Evans Blue ◽  
Blue Dye ◽  
Dependent Manner ◽  
Evans Blue Dye ◽  
Plasma Exudation ◽  
Txa2 Receptor ◽  
Txa2 Receptor Antagonist ◽  
Airway Responses ◽  
Dose Dependent

Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.

Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage

1991 ◽  
Vol 70 (6) ◽  
pp. 2730-2735 ◽  
Author(s):  
J. O. Lotvall ◽  
K. Tokuyama ◽  
C. G. Lofdahl ◽  
A. Ullman ◽  
P. J. Barnes ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Evans Blue ◽  
Enzyme Inhibitors ◽  
Airflow Obstruction ◽  
Neutral Endopeptidase ◽  
Blue Dye ◽  
Enalapril Maleate ◽  
Evans Blue Dye ◽  
Microvascular Leakage ◽  
Degradative Enzymes

We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.

Tumor necrosis factor inhibits a polymorphonuclear leukocyte-dependent airway edema in guinea pigs

1988 ◽  
Vol 64 (4) ◽  
pp. 1688-1692 ◽  
Author(s):  
T. Gordon ◽  
D. Sheppard
Keyword(s):  
Tumor Necrosis Factor ◽  
Evans Blue ◽  
Polymorphonuclear Leukocyte ◽  
Guinea Pigs ◽  
Tumor Necrosis ◽  
Toluene Diisocyanate ◽  
Blue Dye ◽  
Evans Blue Dye ◽  
Airway Edema ◽  
Necrosis Factor

Intravenously administered endotoxin inhibits the polymorphonuclear leukocyte (PMN)-dependent airway edema produced in guinea pigs exposed to toluene diisocyanate (TDI). Tumor necrosis factor (TNF) is produced in vivo by peripheral blood monocytes and tissue macrophages stimulated with endotoxin and has been shown to activate PMN's and vascular endothelial cells. To determine whether the inhibition of airway edema is mediated by TNF, guinea pigs were treated with intravenous saline or 75,000 U/kg recombinant human TNF 1.5 h before exposure to air or 3 ppm TDI for 1 h. Animals were then injected intravenously with 50 mg/kg Evans blue dye as a marker of protein extravasation. Saline-treated animals exposed to TDI had a significant increase in tracheal Evans blue dye extravasation (85 +/- 6.5 micrograms dye/g trachea, mean +/- SE) compared with saline-treated animals exposed to air (31.3 +/- 2.5, P less than 0.001). The tracheal extravasation of Evans blue dye was significantly inhibited (P less than 0.05) in TDI-exposed animals treated with TNF (64.7 +/- 7.5). Neither heat-inactivated TNF (104.9 +/- 9.5) nor TNF neutralized with a monoclonal antibody against TNF (99.7 +/- 17.9) inhibited TDI-induced airway edema. In addition, treatment with 15,000 U/kg (99.9 +/- 21.3) or 150,000 U/kg (103.2 +/- 17.6) interleukin 1, a monokine also produced in response to endotoxin, did not prevent airway edema. These results suggest that TNF released in response to endotoxin mediates endotoxin's inhibition of a PMN-dependent airway edema.

Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs

1997 ◽  
Vol 82 (3) ◽  
pp. 738-745 ◽  
Author(s):  
Junji Hamamoto ◽  
Hirotsugu Kohrogi ◽  
Osamu Kawano ◽  
Hajime Iwagoe ◽  
Kazuhiko Fujii ◽  
...  
Keyword(s):  
Hydrochloric Acid ◽  
Evans Blue ◽  
Guinea Pigs ◽  
Neurogenic Inflammation ◽  
Neutral Endopeptidase ◽  
Blue Dye ◽  
Plasma Extravasation ◽  
Neural Pathways ◽  
Plasma Leakage ◽  
Stimulation Of

Hamamoto, Junji, Hirotsugu Kohrogi, Osamu Kawano, Hajime Iwagoe, Kazuhiko Fujii, Nahomi Hirata, and Masayuki Ando.Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. J. Appl. Physiol. 82(3): 738–745, 1997.—To investigate whether tachykinins are released in the airways in response to stimulation of the esophagus, we studied the airway plasma extravasation induced by intraesophageal HCl in the presence or absence of neutral endopeptidase inhibitor phosphoramidon and NK1-receptor antagonist FK-888 in anesthetized guinea pigs. The airway plasma leakage was evaluated by measuring extravasated Evans blue dye in the animals pretreated with propranolol and atropine. Infusion of 1 N HCl into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation in the trachea and main bronchi, whereas FK-888 significantly inhibited that extravasation in a dose-related manner. In the capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilateral vagotomized animals. These results suggest that 1) tachykinin-like substances are released to cause plasma extravasation in the airways as a result of intraesophageal HCl stimulation and 2) there are neural pathways communicating between the esophagus and airways, including the vagus nerve.

Human urotensin-II enhances plasma extravasation in specific vascular districts in Wistar rats

2004 ◽  
Vol 82 (1) ◽  
pp. 16-21 ◽  
Author(s):  
Gabrielle Gendron ◽  
Bryan Simard ◽  
Fernand Gobeil, Jr. ◽  
Pierre Sirois ◽  
Pedro D'Orléans-Juste ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Evans Blue ◽  
Wistar Rats ◽  
Platelet Activating Factor ◽  
Optimal Dose ◽  
Blue Dye ◽  
Plasma Extravasation ◽  
Urotensin Ii ◽  
Evans Blue Dye

Plasma extravasation (PE) was measured in adult Wistar rats by injecting Evans blue dye (EB) (20 mg kg–1) intravenously in the absence or presence of human urotensin II (U-II) (0.1–10 nmol kg–1). A consistent increase of PE was observed in specific organs (e.g., aorta, from 28.1 ± 2.4 to 74.6 ± 3.6 µg EB g–1 dry tissue; P < 0.001) after an administration of 4.0 nmol kg–1 (a preselected optimal dose) of U-II. The effects of U-II (4.0 nmol kg–1) were compared with those of endothelin-1 (ET-1) (1.0 nmol kg–1). In the thoracic aorta and pancreas, U-II was active, while ET-1 was not. The two agents were equivalent in the heart and kidney, whereas, in the duodenum, ET-1 was more active than U-II. Increases of plasma extravasation induced by U-II, but not by ET-1, were reduced after treatment with [Orn8]U-II (0.3 µmol kg–1). This latter antagonist did not show any significant residual agonistic activity in vivo in the rat. Other specific receptor antagonists for ET-1, such as BQ-123 (endothelin type A (ETA) receptor) and BQ-788 (endothelin type B (ETB) receptor), and for the platelet activating factor (PAF), such as BN50730, failed to modify the action of U-II. The present study is the first report describing the modulator roles of U-II on vascular permeability in specific organs. Moreover, the action of U-II appears specific, since it is independent of the ET-1 and PAF signalling pathways.Key words: urotensin-II, receptors antagonists, Evans blue dye, vascular permeability, rats.

Role of peptidases and NK1 receptors in vascular extravasation induced by bradykinin in rat nasal mucosa

1993 ◽  
Vol 74 (5) ◽  
pp. 2456-2461 ◽  
Author(s):  
C. Bertrand ◽  
P. Geppetti ◽  
J. Baker ◽  
G. Petersson ◽  
G. Piedimonte ◽  
...  
Keyword(s):  
Nasal Mucosa ◽  
Evans Blue ◽  
Sensory Nerve ◽  
Ace Inhibition ◽  
Neutral Endopeptidase ◽  
Blue Dye ◽  
Nk1 Receptor ◽  
Evans Blue Dye ◽  
Neurokinin 1 ◽  
Evans Blue Extravasation

We used Evans blue dye to assess the effects of bradykinin on vascular extravasation in nasal mucosa of pathogen-free F344 rats. There was a dose-dependent increase in Evans blue extravasation when bradykinin was delivered by topical instillation in the nose (doses, 25–100 nmol). Only the highest intravenous doses (2 and 5 mumol/kg) of bradykinin caused increased extravasation. When bradykinin was delivered by either route, its effect on extravasation was exaggerated by pharmacological inhibition of the enzymes neutral endopeptidase (NEP) and kininase II [angiotensin-converting enzyme (ACE)]. When bradykinin was instilled locally, the effect of NEP inhibition was predominant; when bradykinin was injected intravenously, the effect of ACE inhibition was predominant. The mechanism of extravasation also varied with the mode of bradykinin delivery: when bradykinin was instilled locally in the nose, the selective neurokinin 1 (NK1) receptor antagonist CP-96,345 markedly inhibited the response, whereas it had no effect on Evans blue extravasation when bradykinin was injected intravenously. We conclude that bradykinin causes dose-related increases in Evans blue dye extravasation in the nose and that these effects are exaggerated when NEP and ACE are inhibited. Topically instilled bradykinin causes vascular extravasation to a large extent via NK1 receptor stimulation, thus suggesting a major role for tachykinins released from sensory nerve endings.

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