RESUMO
Recent studies indicate that nonsteroidal anti-inflammatory drugs have a chemopreventive effect against colorectal neoplasia. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenases, principal enzymes that mediate the formation of prostanoids. To determine whether prostanoids are involved in the pathogenesis of colorectal adenomas, we compared the levels of five major stable metabolic products of the cyclooxygenase pathway in the normal-appearing mucosa and in adenomas of patients with familial adenomatosis polyposis. Of 12 patients tested, 6 had elevated levels of at least one prostanoid in the adenomas. More importantly, the relative levels of three prostanoids [prostaglandin (PG)D2, PGE2, and 6-keto-PGF1alpha] were elevated in adenomas compared to normal-appearing mucosa from the same patients, and the resulting ratios were correlated with the size of the adenoma. These results suggest a role for prostanoids in progression of colorectal polyposis in familial adenomatosis polyposis patients.
Assuntos
Adenoma/metabolismo , Polipose Adenomatosa do Colo/metabolismo , Prostaglandinas/metabolismo , 6-Cetoprostaglandina F1 alfa/metabolismo , Adenoma/genética , Polipose Adenomatosa do Colo/genética , Adulto , Dinoprosta/metabolismo , Dinoprostona/metabolismo , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ocitócicos/metabolismo , Prostaglandina D2/metabolismo , Tromboxano B2/metabolismoRESUMO
Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.
Assuntos
Inflamação/metabolismo , Pele/metabolismo , Administração Cutânea , Dinoprostona/metabolismo , Liberação de Histamina/efeitos dos fármacos , Humanos , Hidrolases/metabolismo , Hidroxiprolina/metabolismo , Inflamação/induzido quimicamente , Interleucina-1/metabolismo , L-Lactato Desidrogenase/metabolismo , Lisossomos/enzimologia , Mastócitos/metabolismo , Gás de Mostarda/administração & dosagem , Técnicas de Cultura de Órgãos , Proteínas/metabolismo , Pele/citologia , Pele/efeitos dos fármacosRESUMO
Rapid intravenous (IV) injections of the prostaglandin precursor arachidonic acid (AA) increase pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in a variety of species. It has recently been reported that infusions of AA decrease PAP. The purpose of this report is to contrast responses to bolus injections and infusions of AA in the anesthetized dog. In all experiments rapid IV injections of AA increased PAP and PVR; however, infusions of 68 to 680 microgram/min produced variable responses. In 10 of 19 animals, AA infusion decreased PAP and PVR, and this response was enhanced when pulmonary vascular tone was actively increased by vasoconstrictor agents or alveolar hypoxia. In the other nine animals, the predominant response was an increase in PAP and PVR. In all experiments infusions of larger amounts of AA (1.4 to 3.4 mg/min) increased PAP. Both pressor and depressor responses to AA were inhibited to meclofenamate. This study shows that infusion of small amounts of AA dilates or constricts the pulmonary vascular bed. In contrast, infusion of larger amounts of AA always causes vasoconstriction. These data suggest that at low infusion rate, PGI2, which is a vasodilator, is the predominant metabolite formed from AA in some animals. However, at higher concentrations, the production of constrictor products predominates. These experiments also suggest that the products formed and the response observed may be dependent on a number of factors including the amount of tone present in the pulmonary vascular bed.
Assuntos
Ácidos Araquidônicos/farmacologia , Pulmão/efeitos dos fármacos , Prostaglandinas/farmacologia , Animais , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/metabolismo , Cateterismo/instrumentação , Fenômenos Químicos , Química , Cães , Epoprostenol/farmacologia , Feminino , Infusões Parenterais , Injeções Intravenosas , Masculino , Métodos , Prostaglandinas/biossíntese , Prostaglandinas/fisiologia , Circulação Pulmonar/efeitos dos fármacos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
The epithelial cells lining the small, peripheral airways function as important targets for the action of inspired ozone. Loss of epithelial barrier integrity in these regions is a common element in ozone-induced airway inflammation. To investigate the direct effect of ozone on epithelial barrier function, canine bronchial epithelial (CBE) cells grown with an air interface were exposed for 3 hr to 0.2, 0.5, or 0.8 ppm ozone or to air. Mannitol flux, used as an index of paracellular permeability, increased above air controls by 461%, 774%, and 1172% at the three ozone concentrations, respectively. Transcellular electrical resistance exhibited a dose-related decrease. The immediate effect of 0.8 ppm ozone on permeability was significantly inhibited by preincubation for 48 hr in the presence of 1 ng/ml vitamin E (33%) or 1 microM vitamin A (34%). Responses to 0.5 ppm or 0.8 ppm were inhibited by pretreatment of the cells with 0.1 microM of the actin polymerizing agent phalloidin (34% and 25% inhibition, respectively). The increases in permeability induced by 0.2 and 0.5 ppm ozone were attenuated by 54% and 22%, respectively, at 18 hr after exposure, whereas that to 0.8 ppm was further enhanced by 42% at this time. The effects of ozone are modulated by the availability of antioxidants to the cells and appear to be associated with cytoskeletal dysfunction in CBE cells. The data are consistent with a loss of barrier function linked to a direct oxidative effect of ozone on individual CBE cells and indicate that the reversible or progressive nature of this effect is dose dependent.
Assuntos
Brônquios/efeitos dos fármacos , Permeabilidade da Membrana Celular , Ozônio/farmacologia , Animais , Brônquios/metabolismo , Brônquios/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Citocalasina B/administração & dosagem , Citocalasina B/metabolismo , Cães , Relação Dose-Resposta a Droga , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Fluorescência , Manitol/administração & dosagem , Manitol/metabolismo , Ozônio/farmacocinética , Faloidina/administração & dosagem , Faloidina/metabolismo , Vitamina A/administração & dosagem , Vitamina A/metabolismo , Vitamina E/administração & dosagem , Vitamina E/metabolismoRESUMO
In this study, we compared the cytotoxic and genotoxic effects of hydrogen peroxide and ozone on cultured human airway epithelial cells in primary culture. Both agents caused a dose-dependent loss in the replicative ability of epithelial cells and at higher levels of exposure caused acute cytotoxicity as measured by release of lactate dehydrogenase. Differences were seen, however, between the agents' effects with regard to induction of DNA single strand breaks as measured by alkaline elution:; whereas single-strand breaks were detected in significant amounts at concentration of hydrogen peroxide that cause acute cytotoxicity, none were detected at any of the levels of ozone exposure examined. A difference was also seen in the ability of the iron chelator deferoxamine to protect cells from the effect of the two oxidants. Preincubation of cultures with deferoxamine appreciably attenuated the toxicity of hydrogen peroxide but not of ozone. These data suggest that ozone has significant toxic effects on bronchial epithelial cells not mediated through the generation of hydrogen peroxide or hydroxyl radical. Furthermore, the data indicate that the inhibiting action of ozone on cell replicative ability is not mediated through a mechanism related to DNA single strand breaks.
Assuntos
Brônquios/efeitos dos fármacos , Dano ao DNA , DNA/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Ozônio/toxicidade , Brônquios/metabolismo , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Desferroxamina/farmacologia , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , HumanosRESUMO
A review of the literature reveals that ozone (O3) exposure can either suppress or enhance immune responsiveness. These disparate effects elicited by O3 exposure depend, in large part, on the experimental design used, the immune parameters examined as well as the animal species studied. Despite the apparent contradictions, a general pattern of response to O3 exposure can be recognized. Most studies indicate that continuous O3 exposure leads to an early (days 0-3) impairment of immune responsiveness followed, with continued exposures, by a form of adaptation to O3 that results in a re-establishment of the immune response. The effects of O3 exposure on the response to antigenic stimulation also depend on the time at which O3 exposure occurred. Whereas O3 exposure prior to immunization is without effect on the response to antigen, O3 exposure subsequent to immunization suppresses the response to antigen. Although most studies have focused on immune responses in the lung, numerous investigators have provided functional and anatomical evidence to support the hypothesis that O3 exposure can have profound effects on systemic immunity.
Assuntos
Imunidade/efeitos dos fármacos , Ozônio/toxicidade , Animais , Antígenos/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Influenza Humana/imunologia , Tecido Linfoide/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Fagocitose/efeitos dos fármacos , Prostaglandinas/fisiologiaRESUMO
In preliminary studies of antigen-induced airway inflammation, we noted an apparent increase in peribronchiolar mast cell number. Experiments were thus undertaken to investigate the nature of this migration of mast cells into the central and peripheral airway epithelium and to determine its time course. The tracheae and small airways of 10 anesthetized mongrel dogs were exposed via a bronchoscope to Ascaris suum antigen (Ag), fMet-Leu-Phe (fMLP), ovalbumin (OVA), and isotonic saline (SAL). In the central airways, all stimuli provoked a significant increase (P less than 0.05) in mast cell numbers at the base of the airway epithelium within 3 h. In the peripheral airways, only Ag aerosol stimulated a significant mast cell increase compared with unexposed tissue. In a second series of experiments, the trachea of seven dogs were exposed to 0.026, 0.26, and 2.6 micrograms of Ag. The tissue was collected at 1, 3, 6, and 10 h after exposure. In these experiments, there was a significant mast cell increase seen within 1 h but it was not dose dependent. By 6-10 h after exposure, mast cell counts were not significantly different from the unexposed condition, which is consistent with the idea that some of the cells either degranulated or migrated into the airway lumen. We conclude that mast cell migration is an acute response that can be demonstrated within 1 h of stimulation with Ag. The observation that nonimmunological stimuli may, in some cases, also stimulate mast cell movement affords the possibility that this process represents a generalized response to airway irritation.
Assuntos
Mastócitos/citologia , Sistema Respiratório/citologia , Animais , Antígenos de Helmintos/imunologia , Ascaris/imunologia , Contagem de Células , Cães , Inflamação/patologia , Mastócitos/efeitos dos fármacos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Ovalbumina/farmacologia , Sistema Respiratório/efeitos dos fármacosRESUMO
Hypocapnia-induced constriction of peripheral airways may be important in regulating the distribution of ventilation in pathological conditions. We studied the response of the peripheral lung to hypocapnia in anesthetized, paralyzed, mechanically ventilated dogs using the wedged bronchoscope technique to measure resistance of the collateral system (Rcs). A 5-min hypocapnic challenge produced a 161 +/- 19% (mean +/- SE) increase in Rcs. The magnitude of this response was not diminished with repeated challenge or by atropine sulfate (1 mg base/kg iv), chlorpheniramine maleate (5 mg base/kg iv), or indomethacin (5 mg/kg iv). The response was reduced by 75% by isoproterenol (5 micrograms/kg iv) (P less than 0.01) and reduced by 80% by nifedipine (20 micrograms/kg iv) (P less than 0.05). During 30-min exposure to hypocapnia the maximum constrictor response occurred at 4-5 min, after which the response attenuated to approximately 50% of the maximum response (mean = 53%, range 34-69%). Further 30-min challenges with hypocapnia resulted in significantly decreased peak responses, the third response being 50% of the first (P less than 0.001). The inability of indomethacin or propranolol to affect the tachyphylaxis or attenuation of the response suggests that neither cyclooxygenase products nor beta-adrenergic activity was involved. Hence, hypocapnia caused a prompt and marked constrictor response in the peripheral lung not associated with cholinergic mechanisms or those involving histamine H1-receptors or prostaglandins. With prolonged exposure to hypocapnia there was gradual attentuation of the constrictor response with continued exposure and tachyphylaxis to repeated exposure both of which would tend to diminish any compensatory effect of hypocapnic airway constriction on the distribution of ventilation.
Assuntos
Dióxido de Carbono/sangue , Pulmão/fisiopatologia , Taquifilaxia , Resistência das Vias Respiratórias , Animais , Constrição Patológica , Cães , Masculino , Estimulação Química , Taquifilaxia/efeitos dos fármacos , Fatores de TempoRESUMO
We have studied the effect of repeated in vivo antigen exposure on in vitro airway responsiveness in sensitized sheep. Fourteen sheep underwent five biweekly exposures to aerosolized Ascaris suum antigen or saline. Following this exposure regimen, the animals were killed and tracheal smooth muscle and lung parenchymal strips were prepared for in vitro studies of isometric contraction in response to histamine, methacholine, prostaglandin F2 alpha, and a thromboxane A2 analogue. No alteration in tracheal smooth muscle responsiveness was observed between saline- and antigen-exposed tissue. In contrast, by use of lung parenchymal strips as an index of peripheral airway responsiveness, significant increases in responsiveness to histamine and a thromboxane A2 analogue (10(-6) and 10(-5) M) were observed in antigen-exposed tissue compared with saline controls. These results demonstrate that repeated antigen exposure in vivo selectively increase the responsiveness of peripheral lung smooth muscle to certain chemical mediators of anaphylaxis.
Assuntos
Sistema Respiratório/efeitos dos fármacos , Animais , Antígenos/farmacologia , Ascaris/imunologia , Espasmo Brônquico/induzido quimicamente , Dinoprosta , Histamina/farmacologia , Pulmão/efeitos dos fármacos , Cloreto de Metacolina , Compostos de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Prostaglandinas F/farmacologia , Ovinos , Tromboxano A2/farmacologia , Traqueia/efeitos dos fármacosRESUMO
We studied the effects of antigen aerosol challenge on the airways of the canine peripheral lung and examined the roles of cyclooxygenase products, histamine, and cholinergic activity in the responses. One-minute deliveries of 1:10,000 or 1:100,000 concentrations of Ascaris suum antigen aerosol through a wedged bronchoscope resulted in mean maximal increases in collateral system resistance (Rcs) of 415 and 177%, respectively, after 4-8 min. Repeated antigen challenge (1:100,000) resulted in significantly decreased responsiveness to antigen after the initial exposure (P less than 0.005). Bronchoalveolar lavage fluid obtained from the isolated, challenged segment had a significant increase in mean (+/- SE) prostaglandin D2 (PGD2) concentration vs. control (222.0 +/- 65.3 vs. 72.7 +/- 19.5 pg/ml; P less than 0.05); histamine concentrations were variable and not significantly different (4.1 +/- 2.6 vs. 1.2 +/- 0.2 ng/ml; P greater than 0.05). In nine experiments, cyclooxygenase inhibition significantly attenuated the antigen-induced increase in Rcs by 53.4% (P less than 0.001), and the concentration of PGD2 in lavage fluid was reduced by 96.0% (P less than 0.01). Blockade of histamine H1-receptors (n = 8) or cholinergic receptors (n = 7) did not significantly affect the airway response (P greater than 0.05). These data indicate that the canine peripheral lung responds in a dose-dependent manner to antigen aerosol challenge and exhibits characteristics of antigen tachyphylaxis. Results also suggest that cyclooxygenase products play a central role in the acute bronchoconstrictive response of the lung periphery.
Assuntos
Antígenos/administração & dosagem , Pulmão/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Aerossóis , Animais , Antígenos de Helmintos/imunologia , Ascaris/imunologia , Clorfeniramina/farmacologia , Cães , Liberação de Histamina , Indometacina/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Ovalbumina/administração & dosagem , Prostaglandina D2 , Prostaglandinas D/análise , Irrigação TerapêuticaRESUMO
The actions of specific humoral mediators in the immediate response of the canine peripheral airways to antigen challenge are not well understood. Using a method which allows localized exposure of the peripheral lung to antigen, we investigated the role of locally released thromboxane A2 (TxA2) in the immediate response of collateral airways to aerosolized antigen. In dogs with native sensitivity to Ascaris suum antigen, resistance to flow through the collateral system (Rcs) was measured using a wedged bronchoscope technique. Local administration of antigen aerosol (25 microliters, 1:10,000 dilution) produced a gradual increase in Rcs which reached a maximum of 365% of base line in 4-8 min. Analysis of bronchoalveolar lavage fluid obtained from the exposed segment at the peak of the response demonstrated significantly more TxB2 compared with control lavage samples (41.8 +/- 7.8 pg/ml vs. 27.9 +/- 8.3; P less than 0.025). After inhibition of thromboxane synthase with UK-37,248 (3 mg/kg iv) or OKY-046 (5 mg/kg iv), the increase in Rcs was significantly reduced at 40 s (P less than 0.001) and 2 min (P less than 0.01) after antigen delivery, and the maximal increase was attenuated by 41% (P less than 0.005). In contrast, the magnitude and time course of the airway response to aerosols of a stable thromboxane analog (U-46619) were not affected by blockade. Despite a similar attenuation (42%) of the maximal increase in Rcs by sodium meclofenamate (3 mg/kg iv), this cyclooxygenase inhibitor had no effect on the time course of the antigenic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antígenos/imunologia , Brônquios/imunologia , Alvéolos Pulmonares/imunologia , Tromboxano A2/imunologia , Resistência das Vias Respiratórias , Animais , Brônquios/metabolismo , Cães , Masculino , Alvéolos Pulmonares/metabolismo , Irrigação Terapêutica , Tromboxano B2/metabolismo , Tromboxano-A Sintase/antagonistas & inibidores , Fatores de TempoRESUMO
The influence of blood flow through the pulmonary circulation on the time course of recovery of the lung periphery from challenge with three bronchoconstrictive agents was studied in dogs. The rate of perfusion of the left lower lobe was varied between 0 and 300 ml/min. A fiber-optic bronchoscope (OD = 5.5 mm) was wedged in a small airway in the same lobe, and resistance to airflow through the collateral system was continuously monitored. The lung was challenged with histamine aerosol for 1 min, or with intravenous boluses of histamine, acetylcholine, or methacholine. The time constant (tau) of recovery from each of the challenges was measured under the various pulmonary blood flow conditions. The mean tau of the recoveries from histamine was inversely related to the rate of blood flow. However, pulmonary blood flow had no effect on recovery from challenge with acetylcholine or methacholine, two agents metabolized by cholinesterase in lung tissue. From this study we conclude that recovery of the lung periphery from histamine is perfusion dependent, whereas recovery from acetylcholine or methacholine is perfusion independent. This suggests that the rate of blood flow through the pulmonary circulation could play an important role in recovery of the peripheral airways from certain mediators of bronchoconstriction.
Assuntos
Brônquios/fisiopatologia , Circulação Pulmonar , Acetilcolina/farmacologia , Animais , Brônquios/efeitos dos fármacos , Constrição Patológica , Cães , Histamina/farmacologia , Masculino , Cloreto de Metacolina , Compostos de Metacolina/farmacologia , PerfusãoRESUMO
We investigated the effect of eliminating the bronchial circulation on recovery time from intravenous histamine challenge in canine lung periphery. Results from animals with intact bronchial circulations were compared with a second group in which the left lower lobe was isolated in situ. The pulmonary artery to this lobe was perfused and a bronchoscope was wedged in a small airway, which provided an index of resistance to airflow through the collateral system. The lobe was challenged with intravenous histamine, and the time constant of recovery (tau) from bronchoconstriction was measured. With or without pulmonary blood flow, elimination of the bronchial circulation increased tau 44.4 and 48.5%, respectively. This increase was similar to that found by stopping pulmonary blood flow alone (56.5%). Histamine challenges were also performed in sympathectomized or vagotomized animals with intact bronchial circulations. Neither of these conditions increased tau. We conclude that blood flow through the bronchial circulation affects the recovery time from intravenous histamine challenge in the lung periphery to a degree similar to that of the pulmonary circulation.
Assuntos
Brônquios/irrigação sanguínea , Espasmo Brônquico/fisiopatologia , Animais , Cães , Masculino , Fisiologia/instrumentação , Circulação Pulmonar , Fluxo Sanguíneo Regional , Reserpina/farmacologia , VagotomiaRESUMO
The present study was undertaken to determine whether beta-adrenoceptors could be physiologically detected in the lung periphery and whether they were under tonic stimulation in the resting state in anesthetized dogs. A fiberoptic bronchoscope was wedged in a sublobar segment of lung in anesthetized male mongrel dogs for measurement of resistance through the collateral system (Rcs). beta-Agents were delivered locally as aerosols through the bronchoscope, and the response was evaluated by changes in Rcs. Distilled water alone produced a mean increase of 8.5 +/- 2.43% (SE) in Rcs at 2 min in six dogs, whereas dl-isoproterenol produced a mean decrease of 8.9 +/- 2.10% (P less than 0.03), thus demonstrating the presence of submaximally stimulated beta-receptors. To test whether the beta-receptors were under tonic stimulation, we compared the effect of aerosolized d- and dl-propranolol in 5 dogs. d-Propranolol that lacks significant beta-blocking activity and dl-propranolol both produced large transient increases in Rcs. However, with d-propranolol, Rcs had returned to base line at 15 min, whereas with dl-propranolol Rcs remained elevated at a mean of 20% above base line for greater than 2 h (P less than 0.01). Local timolol aerosol also produced a sustained increase in Rcs. After pretreatment with reserpine or after bilateral adrenalectomy, both d- and dl-propranolol still produced large transient increases in Rcs, but dl-propranolol no longer produced a sustained increase. Neither isoproterenol nor atropine affected Rcs in the presence of dl-propranolol, nor did pretreatment with atropine affect the response of Rcs to dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Isoproterenol/farmacologia , Pulmão/inervação , Receptores Adrenérgicos beta/fisiologia , Sistema Nervoso Simpático/fisiologia , Adrenalectomia , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Atropina/farmacologia , Cães , Masculino , Propranolol/farmacologia , Estereoisomerismo , Timolol/farmacologiaRESUMO
We studied the effects of repeated exposures of antigen on airway reactivity to mediators of anaphylaxis and immediate response to the antigen. Seven antigen-sensitive sheep were exposed to aerosols of Ascaris suum antigen 5 times biweekly; a control group of seven sheep underwent the same exposure regimen with saline vehicle. Sheep were assigned to experimental (Ascaris) or control groups so the distribution of animals with regard to bronchial reactivity to mediators was about the same. Airway reactivity was assessed by determining the effects of aerosolized histamine (10-1,000 micrograms), prostaglandin F2 alpha (PGF2 alpha, 10-300 micrograms), and a stable analogue of thromboxane A2 (U-46619, 1-100 micrograms) on lung resistance (RL) and dynamic lung compliance (Cdyn). Before treatment, experimental and control groups showed similar changes in RL and Cdyn, with analogue greater than histamine greater than PGF2 alpha. At the highest dose of each agonist, mean increases in RL were 50, 123, and 29%, respectively, and mean decreases in Cdyn were 21, 45, and 12%. During the first 15-min exposures to antigen aerosol, mean RL had increased by 125% and Cdyn decreased by 38% of base-line values; hyperinflation following the exposures reduced the changes to 56 and 31%, respectively. Changes in RL and Cdyn during the final antigen exposures and following postexposure hyperinflation were reduced significantly (P less than 0.05) compared with the initial exposures. Baseline RL and Cdyn before and after the exposures to antigen or saline were not significantly different. Airway reactivity to histamine, PGF2 alpha, or analogue was not significantly altered in these atropinized animals over the range of doses studied.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Testes de Provocação Brônquica , Espasmo Brônquico/induzido quimicamente , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Antígenos , Ascaris/imunologia , Dinoprosta , Relação Dose-Resposta a Droga , Histamina/farmacologia , Pulmão/citologia , Mastócitos , Neutrófilos , Prostaglandinas F/farmacologia , Ovinos , Testes CutâneosRESUMO
We investigated the time course and regional distribution of the expression of intercellular adhesion molecule-1 (ICAM-1) on airway epithelial cells and the polymorphonuclear leukocyte (PMN) inflammatory response in the lung after acute exposure to ozone (O3). C57BL/6J mice were exposed to air or 2 ppm O3 for 3 h and killed immediately or 3, 6, 9, or 21 h after exposure. Expression of ICAM-1 was examined by immunohistochemical staining of frozen sections. PMN influx was evaluated by lavage and by histochemical staining of myeloperoxidase (MPO) and measurement of tissue MPO activity. ICAM-1 expression exhibited regional selectivity and temporal patterns that were unique to each region. Upregulation of ICAM-1 expression on the epithelial cells in the trachea, and to a lesser extent in the lobar and segmental bronchi, was observed 3-9 h after exposure and remained present at 21 h. Enhanced ICAM-1 expression in bronchioles and terminal bronchiole/alveolar duct regions was evident earlier (immediately to 3 h after exposure) but returned to baseline levels by 21 and 9 h, respectively. Maximal ICAM-1 expression and PMN influx in the lung parenchyma were concurrently observed at 3 h, followed by transepithelial migration of PMNs to the airway lumen. These results demonstrate regional variations in airway inflammatory activity and are supportive of the notion that upregulation of ICAM-1 on the airway epithelium may play a role in local regulation of PMN influx to the airways after acute O3 exposure.
Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Neutrófilos/metabolismo , Oxidantes Fotoquímicos/farmacologia , Ozônio/farmacologia , Sistema Respiratório/metabolismo , Administração por Inalação , Animais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologiaRESUMO
Cardiac norepinephrine (NE) levels exhibit a marked reduction in rats suffering from hemolytic anemia induced with antibodies against rat red blood cells. Administration of antiserum via tail vein resulted in a highly reproducible 70% drop in hemoglobin levels by 72 h. At 96 h cardiac NE levels were decreased by 67%; NE levels in vas deferens and submaxillary gland were not decreased. Within 10 days, both hemoglobin and cardia NE returned to near control levels. Hearts from anemic rats showed a 68% decrease in their ability to accumulate 3H-NE administered in tracer doses at 72 h of anemia. Cardiac NE turnover rates were increased 88% in 72 h anemic animals. These results are consistent with an anemia-induced activation of cardiac sympathetic nerves. Cardiac monoamine oxidase and dopamine-beta-hydroxylase activities in whole heart homogenates were similar in control and anemic animals at 72 h. These results suggest that NE depletion is not the result of decreased synthetic capacity of the nerves or degeneration of existing terminals. The data suggest that cardiac NE depletion during anemic stress is associated with the combined effects of increased NE release and a decrease in the effective NE uptake or binding capacity of sympathetic nerves. Anemia-induced depletion may, therefore, be different from the depletion associated with other forms of cardiovascular stress.
Assuntos
Anemia/fisiopatologia , Coração/inervação , Sistema Nervoso Simpático/fisiopatologia , Animais , Eritrócitos/imunologia , Hemoglobinas/metabolismo , Cinética , Masculino , Miocárdio/enzimologia , Norepinefrina/metabolismo , RatosRESUMO
Recent studies indicate that sulindac, a nonsteroidal anti-inflammatory drug (NSAID), lowers mucosal prostanoid levels and regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP). To determine whether they are biomarkers for sulindac-mediated chemoprevention of colorectal adenomas, levels of 5 prostanoids [prostaglandin (PG) D2, PGE2, PGF2alpha, thromboxane B2, and 6-keto-PGF1alpha] in the normal-appearing rectal mucosa from 7 FAP patients with a history of subtotal colectomy and ileorectal anastomosis and 4 FAP patients without surgery, were measured in the absence or presence of exogenously added arachidonic acid before the initiation and at the end of 3 months of sulindac treatment. The addition of arachidonic acid resulted in a uniform increase in the levels of all 5 prostanoids although this increase was selectively attenuated in patients with ileorectal anastomosis who took sulindac. In the latter patients, arachidonic acid also augmented the inhibition of prostanoid synthesis by sulindac. In contrast, sulindac failed to attenuate the increase in prostanoid levels resulting from arachidonic acid in patients without previous surgery. Importantly, when measured in the presence of arachidonic acid, the reduction in the levels of all 5 prostanoids due to sulindac was statistically correlated with a reduction in the size and number of adenomas in the two groups of patients combined. These results suggest that tissue prostanoids measured in the presence of arachidonic acid may serve as sensitive and reliable biomarkers in monitoring the clinical responsiveness of FAP patients undergoing chemoprevention for colorectal neoplasia with NSAIDs.