RESUMO
Infections and infectious complications are the major cause of morbidity and mortality in febrile neutropenic patients after autologous stem cell transplantation. Laboratory biomarkers are helpful for early identification of critically ill patients and optimal therapy management. Several studies in adult non-neutropenic patients proposed sTREM-1 as a superior biomarker for identification of septic patients as well as a predictor for survival in these patients compared with procalcitonin (PCT), C-reactive protein (CRP), or interleukin-8 (IL-8). Here, to assess the utility of PCT, CRP, IL-8, and sTREM-1 in febrile neutropenia, 44 patients presenting with febrile neutropenia after autologous stem cell transplantation were recruited in a single-center prospective pilot study. We analyzed PCT and CRP as well as IL-8 and sTREM-1 levels pre- and post-transplantation at defined time points. In 20 of 44 patients, concentration of sTREM-1 was under the detection level at appearance of febrile neutropenia. Mean levels of PCT, IL-8, and CRP were significantly increased in infections of critically ill patients who by dysfunction or failure of one or more organs/system depend on survival from advanced instruments of monitoring and therapy. However, all tested biomarkers could not distinguish between presence and absence of bloodstream infection. The combination of the biomarkers PCT and IL-8 achieved a high sensitivity of 90% and specificity of 74% for the identification of serious complications in febrile neutropenia, whereas the combination of CRP and PCT or IL-8 achieved a high sensitivity of 100%, but with the addition of a low specificity of 47or 41%. In conclusion, we found that the measurement of sTREM-1 concentration at presentation of febrile neutropenia is not useful to identify bacterial bloodstream infections and critically ill patients. PCT and IL-8 are useful biomarkers for the early identification of critically ill patients, compared to CRP and sTREM-1 in febrile neutropenia. PCT or IL-8 in combination with clinical parameters should be considered in routine measurement to identify critically ill patients as early as possible.
Assuntos
Proteína C-Reativa/metabolismo , Calcitonina/sangue , Neutropenia Febril , Interleucina-8/sangue , Transplante de Células-Tronco , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Idoso , Autoenxertos , Estado Terminal , Neutropenia Febril/sangue , Neutropenia Febril/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.
Assuntos
Orelha Interna/metabolismo , Fibroblastos/metabolismo , Gelatinases/biossíntese , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/genética , Rim/metabolismo , Proteínas de Membrana , Metaloendopeptidases/biossíntese , Proteínas/genética , Animais , Células Cultivadas , Cóclea/enzimologia , Cóclea/metabolismo , Orelha Interna/enzimologia , Ativação Enzimática/genética , Repressão Enzimática/genética , Fibroblastos/enzimologia , Genes Recessivos , Glomerulosclerose Segmentar e Focal/enzimologia , Humanos , Rim/citologia , Rim/enzimologia , Metaloproteinase 2 da Matriz , Camundongos , Camundongos Mutantes , Biossíntese de ProteínasRESUMO
Immunohistology for expression of the CD3zeta and CD3epsilon chains in TIL was performed in 138 paraffin-embedded primary oral squamous cell carcinoma tissues and 10 nontumor, inflammatory lesions. Semiquantitative analysis of the staining intensity for zeta chain expression and number of zeta chain expression-positive cells distinguished tumors with absent or low zeta expression (42 of 132) from those with normal zeta expression (90 of 132). Zeta chain expression was inversely correlated with the tumor stage. Survival was significantly lower in patients whose TIL had absent or low zeta expression, controlling for stage (P = 0.003) and lymph node status (P = 0.0005). The prognostic value of zeta chain was restricted to patients with stage III or IV tumors (P = 0.003). The data indicate that absent or decreased zeta expression in TIL combined with tumor stage or nodal status defines a group of patients with oral squamous cell carcinoma who have an extremely poor prognosis.
Assuntos
Complexo CD3/biossíntese , Carcinoma de Células Escamosas/metabolismo , Proteínas de Membrana/biossíntese , Neoplasias Bucais/embriologia , Receptores de Antígenos de Linfócitos T/biossíntese , Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/ultraestruturaRESUMO
Although a role for the airway circulation in the clearance of inhaled particles is generally assumed, there is little information to confirm its importance. We studied the effects of decreased bronchial blood flow on the uptake of the soluble tracer technetium=99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) from subcarinal airways in sheep (n = 7). The bronchial artery was cannulated and perfused with autologous blood at a control flow (0.6 mL/min/kg) or when the perfusion pump was stopped (no flow). (99m)Tc-DTPA (6-10 microL) was delivered by a microspray nozzle inserted through a bronchoscope to a fourth-generation bronchus both during control blood flow conditions and no-flow conditions. Airway retention (by scintigraphy) and blood uptake were monitored for 30 min after the local deposition of (99m(Tc-DTPA. During control flow conditions, 30 min after the delivery of the radiolabel, 21% of the tracer remained at the deposition site. Of the total delivered tracer, maximum blood uptake was 18% (n) = 3). When bronchial perfusion was stopped, airway retention 30 min after deposition increased to 43%, and maximum blood uptake decreased to 7% of the total delivered tracer. Although mucociliary clearance was not directly measured, radiolabel tracer was observed to move progressively from the deposition site up to larger airways and contributed to the overall removal of tracer from the site of deposition during both flow conditions. However, these results demonstrate that decreased bronchial perfusion increases airway retention by limiting vascular uptake of the soluble tracer. These results emphasize the importance of normal perfusion of the airway vasculature for uptake of therapeutic agents delivered specifically to the conducting airways.
Assuntos
Brônquios/irrigação sanguínea , Artérias Brônquicas/fisiologia , Compostos Radiofarmacêuticos/farmacocinética , Pentetato de Tecnécio Tc 99m/farmacocinética , Animais , Brônquios/diagnóstico por imagem , Brônquios/metabolismo , Artérias Brônquicas/diagnóstico por imagem , Modelos Animais , Fluxo Pulsátil , Cintilografia , Compostos Radiofarmacêuticos/sangue , Fluxo Sanguíneo Regional , Ovinos , Pentetato de Tecnécio Tc 99m/sangueRESUMO
Numerous mediators of inflammation have been demonstrated to cause airway microvascular fluid and protein extravasation. That fluid extravasation results in airway wall edema leading to airway narrowing and enhanced reactivity has not been confirmed. In anesthetized, ventilated sheep (n = 30), airway vascular fluid extravasation was induced by infusing bradykinin (10(-6) M) through a cannulated, blood-perfused bronchial artery. Airway wall edema and luminal narrowing were determined morphometrically. Airway reactivity to methacholine (MCh; 10 microg/ml, intrabronchial artery) was determined by measuring conducting airway resistance (Raw) by forced oscillation. Raw measurements were made and lung lobes were excised and quick frozen before or after a 1-h bradykinin infusion. In 10 airways per lobe (range 0.2- to 2.0-mm relaxed diameter), wall area occupied 32 +/- 2% (SE) of the total normalized airway area (n = 9). Bradykinin infusion increased wall area to 42 +/- 5% (P = 0.02); luminal area decreased by <5%; and smooth muscle perimeter, a measure of smooth muscle constriction, was not altered (n = 5). Raw showed no change from baseline (1.4 +/- 0.4 cmH2O . l-1 . s) after bradykinin infusion (n = 10). During MCh challenge, Raw increased by 3.2 +/- 04 cmH2O . l-1 . s, and this change did not differ after administration of bradykinin. MCh challenge caused similar decreases in smooth muscle perimeter (10%) and luminal area (72 vs. 68%) before and after bradykinin infusion. However, the time constant of recovery of Raw from MCh constriction was increased from control (40 +/- 3 s) to 57 +/- 10 s after bradykinin infusion (P = 0.03). When lung lobes were excised at the same time after MCh challenge was terminated (n = 5), luminal area was greater before bradykinin infusion than after (86 vs. 78%; P = 0.007), as was smooth muscle perimeter. The results of this study demonstrate that airway wall edema limits relaxation after induced constriction rather than enhancing constriction.
Assuntos
Brônquios/fisiopatologia , Edema Pulmonar/fisiopatologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Bradicinina/farmacologia , Brônquios/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Agonistas Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Edema Pulmonar/induzido quimicamente , OvinosRESUMO
We studied the effect of systemic hypoxia on the bronchial vascular pressure-flow relationship in anesthetized ventilated sheep. The bronchial artery, a branch of the bronchoesophageal artery, was cannulated and perfused with a pump with blood from a femoral artery. Bronchial blood flow was set so bronchial arterial pressure approximated systemic arterial pressure. For the group of 25 sheep, control bronchial blood flow was 22 ml/min or 0.7 ml.min-1.kg-1. During the hypoxic exposure, animals were ventilated with a mixture of N2 and air to achieve an arterial PO2 (PaO2) of 30 or 45 Torr. For the more severe hypoxic challenge, bronchial vascular resistance (BVR), as determined by the slope of the linearized pressure-flow curve, decreased acutely from 3.8 +/- 0.4 mmHg.ml-1.min to 2.9 +/- 0.3 mmHg.ml-1.min after 5 min of hypoxia. However, this vasodilation was not sustained, and BVR measured at 30 min of hypoxia was 4.2 +/- 0.8 mmHg.ml-1.min. The zero flow intercept, an index of downstream pressure, remained unaltered during the hypoxic exposure. Under conditions of moderate hypoxia (PaO2 = 45 Torr), BVR decreased from 4.6 +/- 0.3 to 3.8 +/- 0.4 mmHg.ml-1.min at 5 min and remained dilated at 30 min (3.6 +/- 0.5 mmHg.ml-1.min). To determine whether dilator prostaglandins were responsible for the initial bronchial vascular dilation under conditions of severe hypoxia (PaO2 approximately equal to 30 Torr), we studied an additional group of animals with pretreatment with the cyclooxygenase inhibitors indomethacin (2 mg/kg) and ibuprofen (12.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Brônquios/irrigação sanguínea , Hipóxia/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Artérias Brônquicas/fisiopatologia , Ibuprofeno/farmacologia , Indometacina/farmacologia , Masculino , Prostaglandinas/fisiologia , Ovinos , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Although a role for the bronchial circulation in clearance of bronchoactive agents has been frequently proposed, experimental evidence is limited. In this study, we determined the importance of bronchial blood flow (QBA) in the recovery from methacholine-(MCh) induced bronchoconstriction. In 10 pentobarbital-anesthetized ventilated sheep, the bronchial branch of the bronchoesophageal artery was cannulated and perfused (0.7 ml.min-1.kg-1) with blood pumped from the femoral artery. MCh was infused directly into the bronchial artery at increasing concentrations (10(-7) to 10(-5) M). MCh infusion caused a concentration-dependent increase in airway resistance at constant QBA. However, the time constant of recovery (TC) from airway constriction after cessation of the MCh infusion was not dependent on the MCh concentration or the magnitude of the increases in airway resistance. When QBA was at 50, 100, and 200% of control level, with constant MCh concentration, TC was 44 +/- 6, 25 +/- 2, and 24 +/- 2 (SE) s at each flow level, respectively. TC at 50% of control QBA was significantly greater than at control QBA (P less than 0.01). Thus the magnitude of QBA can alter the time course of recovery from MCh-induced increases in airway resistance. These results document the importance of QBA in reversing agonist-induced constriction and suggest that an impaired bronchial circulation may contribute to the mechanism of airway hyperreactivity.
Assuntos
Brônquios/irrigação sanguínea , Broncoconstrição/fisiologia , Compostos de Metacolina/farmacologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Artérias Brônquicas/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Infusões Intravenosas , Masculino , Fluxo Sanguíneo Regional/efeitos dos fármacos , OvinosRESUMO
We studied the bronchial vascular response to downstream pressure elevation by increasing left atrial pressure (Pla) and mean airway pressure (Paw) with positive end-expiratory pressure (PEEP). In seven pentobarbital-anesthetized ventilated sheep, we cannulated and perfused the bronchial branch of the bronchoesophageal artery. Steady-state bronchial artery pressure- (Pba) flow (Qba) relationships were obtained as Pla was increased by inflating a balloon catheter in the left atrium. Bronchial vascular resistance (BVR), determined by the inverse slope of the Pba-Qba relationship, increased significantly from 3.2 +/- 0.3 (SE) mmHg.ml-1.min-1 at a Pla of 2.9 +/- 0.7 mmHg to 5.1 +/- 0.5 mmHg.ml-1.min-1 at a Pla of 20.1 +/- 2.0 mmHg (P = 0.0007). Under control Qba (23.3 +/- 1.2 ml/min), these changes in BVR represent a 3.6 +/- 0.7-mmHg increase in Pba per mmHg increase in Pla. The zero-flow pressure increased 1.3 +/- 0.2 mmHg/mmHg increase in Pla. After infusion of papaverine, a smooth muscle paralytic agent, directly into the bronchial artery, BVR decreased significantly to 1.3 +/- 0.7 mmHg.ml-1.min-1 (P = 0.0004). Under these dilated conditions, BVR was unaltered by increases in Pla. After papaverine administration, Pba increased 0.9 +/- 0.1 and 1.2 +/- 0.1 mmHg/mmHg increase in Pla during control and zero-flow conditions, respectively. Thus the effect of Pla elevation on BVR appears to be dependent on active smooth muscle responses. Paw elevation had similar effects on Pba. Under control Qba, Pba increased 2.2 +/- 0.4 mmHg/mmHg increase in Paw.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Função Atrial , Pressão Sanguínea/fisiologia , Brônquios/irrigação sanguínea , Resistência das Vias Respiratórias/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Papaverina/farmacologia , Respiração com Pressão Positiva , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Ovinos , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologiaRESUMO
Bronchial arterial (BA) perfusion could modify pulmonary arterial (PA) ischemia-reperfusion (IR) injury by promoting clearance of peribronchial edema or limiting edema formation through maintenance of pulmonary vessel integrity via bronchopulmonary anastomotic or pulmonary vasa vasorum flow. The purpose of this study was to determine the effect of BA perfusion on IR injury in isolated sheep lungs. In 12 lungs (BA++) the BA was perfused throughout 30 min of PA ischemia and 180 min of reperfusion. In 12 lungs (BA-+) BA perfusion was begun with PA reperfusion, and in 15 lungs (BA--) the BA was never perfused. After 180 min, extravascular lung water was less (P < 0.05) in BA++ and B-+ lungs [4.70 +/- 0.16 and 4.57 +/- 0.18 g/g blood-free dry lung (bfdl)] than in BA-- lungs (5.23 +/- 0.19 g/g bfdl). The reflection coefficient for albumin was greater (P < 0.05) in BA++ and BA-+ (0.57 +/- 0.06 and 0.75 +/- 0.03) than in BA-- lungs (0.44 +/- 0.04). The filtration coefficient in BA++ and BA-+ lungs (0.016 +/- 0.006 and 0.015 +/- 0.006 g.min-1 x mmHg-1 x kg-1) was not different from that in BA-- lungs (0.025 +/- 0.006 g.min-1 x mmHg-1 x kg-1). These results suggest that BA perfusion decreased reperfusion edema by attenuating the increase in pulmonary vascular permeability caused by IR injury. Moreover the result in BA-+ lungs suggests that the protective effect was mediated by BA perfusion of PA vasa vasorum rather than bronchopulmonary anastomotic flow, which was trivial compared with PA blood flow.
Assuntos
Brônquios/irrigação sanguínea , Pulmão/fisiologia , Traumatismo por Reperfusão/fisiopatologia , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Artérias Brônquicas/fisiologia , Permeabilidade Capilar/fisiologia , Água Extravascular Pulmonar/fisiologia , Isquemia/fisiopatologia , Sistema Linfático/fisiologia , Circulação Pulmonar/fisiologia , Edema Pulmonar/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Respiração Artificial , Ovinos , Tromboxano B2/metabolismo , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.
Assuntos
Brônquios/irrigação sanguínea , Compostos Radiofarmacêuticos/farmacocinética , Pentetato de Tecnécio Tc 99m/farmacocinética , Animais , Pressão Sanguínea , Brônquios/metabolismo , Artérias Brônquicas , Processamento de Imagem Assistida por Computador , Depuração Mucociliar , Perfusão , Fluxo Sanguíneo Regional , OvinosRESUMO
Airway wall edema, prominent in inflammatory airways disease, may alter barrier properties at the airway air-liquid interface such that normal absorption of soluble substances into the airway circulation is altered. We studied the effects of bradykinin-induced airway wall edema on the clearance of the soluble tracer technetium-99m-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) from subcarinal airways in sheep (n = 8). (99m)Tc-DTPA (6-10 microl) was delivered by a microspray nozzle inserted through a bronchoscope to a fourth-generation bronchus both before and 1 h after bradykinin (20 ml; 10(-6) M) had been infused through a cannulated and perfused bronchial artery. Airway retention (by scintigraphy) and blood levels of radiolabel were monitored for 30 min after the local deposition of (99m)Tc-DTPA. During control conditions, 85-90% of the tracer cleared from the deposition site within 30 min. The maximum blood level during that time was 17% of the total delivered tracer. However, 1 h after bradykinin infusion, there was significant retention of the marker at the deposition site with clearance within 30 min reduced to 63-70% and decreased blood levels of radiolabel (8%; both P < 0.05). These results demonstrate that moderate airway wall edema alters blood uptake and removal of soluble substances delivered to the subcarinal airways. We suggest that the interplay between vascular and mucociliary clearance routes will impact the resident time for clearance of soluble air toxins and/or therapeutic agents from the epithelial surface.
Assuntos
Brônquios/metabolismo , Edema Pulmonar/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Pentetato de Tecnécio Tc 99m/farmacocinética , Animais , Bradicinina , Brônquios/diagnóstico por imagem , Depuração Mucociliar , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/diagnóstico por imagem , Cintilografia , Compostos Radiofarmacêuticos/sangue , Valores de Referência , Ovinos , Pentetato de Tecnécio Tc 99m/sangueRESUMO
Airway vascular engorgement has been suggested to cause luminal narrowing and airflow obstruction. To determine the extent to which changes in bronchial vascular volume could influence airway dimensions, we studied the effects of left atrial pressure elevation on airway morphometry in sheep (n = 17). The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood (0.6 ml.min-1.kg-1). A balloon-tipped catheter was inserted into the left atrial appendage to elevate left atrial pressure by 10 mmHg, and papaverine was infused into the bronchial artery to eliminate airway smooth muscle tone. Morphological measurements were made from rapidly frozen lungs excised in vivo. Left atrial pressure elevation caused a 79% increase in total vascular area (P = 0.0002). Average airway luminal area was significantly decreased from 86 to 71% of the airway maximal area (P < 0.0001). Noteworthy were the prominent bronchial vessels located within mucosal folds. However, when papaverine was infused during left atrial pressure elevation, despite a comparable total vascular area, luminal narrowing did not occur and remained at 87% of the maximal area (P = 0.6267). In conclusion, we found that engorgement of the bronchial vasculature leads to an increase in the vascular area in regions inside and outside the smooth muscle layer. The associated decrease in luminal area only occurs in the presence of airway smooth muscle tone. This suggests a reflex effect on the airway caused by the vascular engorgement. We conclude that vascular engorgement of the airway wall per se has a negligible effect on airway obstruction.
Assuntos
Brônquios/anatomia & histologia , Brônquios/irrigação sanguínea , Sistema Respiratório/anatomia & histologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Anestesia Geral , Animais , Função Atrial , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Brônquios/efeitos dos fármacos , Capacidade Residual Funcional , Átrios do Coração/efeitos dos fármacos , Cinética , Tono Muscular/fisiologia , Músculo Liso/anatomia & histologia , Músculo Liso/fisiologia , Papaverina/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Sistema Respiratório/efeitos dos fármacos , Ovinos , Vasodilatadores/farmacologiaRESUMO
The role of the airway circulation in supporting mucociliary function has been essentially unstudied. We evaluated the airway clearance of inert, insoluble particles in anesthetized ventilated sheep (n = 8), in which bronchial perfusion was controlled, to determine whether airway mucosal blood flow is essential for maintaining surface transport of particles through airways. The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood at control flow (0.6 ml.min-1.kg-1) or perfusion was stopped. With the sheep in a supine position and after a steady-state 133Xe ventilation scan for designation of lung zones of interest, an inert 99mTc-labeled sulfur colloid aerosol (2.1-microns diameter) was deposited in the lung. The clearance kinetics of the radiolabeled particles were determined from the activity-time data obtained for right and left lung zones. At 60 min postdeposition of aerosol, average airway particle retention for control bronchial blood flow conditions was 57 +/- 7 (SE)% for the right and 53 +/- 8% for the left lung zones. Clearance of particles was significantly impaired when bronchial blood flow was stopped, e.g., right and left lung zones averaged 77 +/- 6 and 76 +/- 7% at 60 min, respectively (P < 0.05). These data demonstrate a significant influence of the bronchial circulation on mucociliary transport of insoluble particles. Potential mechanisms that may account for these results include the importance of the bronchial circulation for nutrient flow, maintenance of airway wall temperature and humidity, and release of mediators and sequelae associated with tissue ischemia.
Assuntos
Pulmão/fisiologia , Depuração Mucociliar/fisiologia , Sistema Respiratório/irrigação sanguínea , Aerossóis , Animais , Brônquios/irrigação sanguínea , Pulmão/diagnóstico por imagem , Cintilografia , Fluxo Sanguíneo Regional/fisiologia , Mecânica Respiratória/fisiologia , Ovinos , Coloide de Enxofre Marcado com Tecnécio Tc 99m , Radioisótopos de XenônioRESUMO
Recent studies suggest a significant contribution of the pulmonary circulation to the perfusion of large airways. In this study we used anesthetized ventilated sheep (n = 19) to determine the functional contribution of the pulmonary circulation to airway smooth muscle. We performed sequential intravenous challenge with methacholine chloride (MCh; 0.25-2.5 mg/ml) to determine airway resistance (Raw) changes in the intact animal, after bronchial artery cannulation that essentially removed bronchial arterial delivery of MCh, and in an isolated lung preparation. After blocking the vagal reflex component of this response, we found that intravenous MCh in the intact preparation resulted in an average 2.2 +/- 0.5 cmH2O.l-1.s increase (181%) in Raw. After prevention of bronchial arterial delivery of MCh, Raw increased by 0.8 +/- 0.3 cmH2O.l-1.s (64%; P < 0.01 compared with intact preparation). In the isolated lung preparation, Raw increased by 0.6 +/- 0.2 cmH2O.l-1.s (63%; P < 0.01 compared with intact preparation). These results demonstrate that in sheep, the bronchial artery provides the major route for delivery of intravenously administered agonists to airway smooth muscle. Considering the large dilutional effect of an intravenously administered agonist by the time it reaches the bronchial artery, we conclude that the pulmonary component of agonist delivery to large airways is < 10% and unlikely to play a major physiological role.
Assuntos
Músculo Liso/irrigação sanguínea , Circulação Pulmonar/fisiologia , Sistema Respiratório/irrigação sanguínea , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Técnicas In Vitro , Masculino , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/farmacologia , Músculo Liso/efeitos dos fármacos , Perfusão , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Sistema Respiratório/efeitos dos fármacos , Ovinos , VagotomiaRESUMO
To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial artery or as an aerosol via tracheostomy into the lower airways. We then measured the contraction of an isolated, in situ segment of trachealis smooth muscle and determined the effect of vagotomy on the trachealis response. Administering methacholine to the subcarinal airways via the bronchial artery (0.5-10.0 microg/ml) caused dose-dependent bronchoconstriction and contraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased an average of 186% over baseline. Aerosolized methacholine (5-7 breaths of 100 mg/ml) increased trachealis tension by 58% and airways resistance by 183%. As the bronchial circulation in the sheep does not supply the trachea, we postulated that the trachealis contraction was caused by a reflex response to methacholine in the lower airways. Bilateral vagotomy essentially eliminated the trachealis response and the airways resistance change after lower airways challenge (either via the bronchial artery or via aerosol) with methacholine. We conclude that 1) methacholine causes a substantial reflex contraction of airway smooth muscle and 2) the assumption may not be valid that a response to methacholine in humans or experimental animals represents solely the direct effect on smooth muscle.
Assuntos
Brônquios/efeitos dos fármacos , Broncoconstritores/farmacologia , Cloreto de Metacolina/farmacologia , Reflexo/efeitos dos fármacos , Aerossóis , Animais , Brônquios/irrigação sanguínea , Broncoconstritores/administração & dosagem , Infusões Intra-Arteriais , Cloreto de Metacolina/administração & dosagem , Fluxo Sanguíneo Regional/efeitos dos fármacos , Músculos Respiratórios/irrigação sanguínea , Músculos Respiratórios/efeitos dos fármacos , Músculos Respiratórios/fisiologia , Ovinos , Nervo Vago/fisiologiaRESUMO
It has been suggested that airway obstruction may be mediated in part by airway vascular engorgement or airway wall edema. However, there are few data that support this conjecture. In this study we examined the effects of increased bronchial blood flow (Qba) on airway wall dimensions, conducting airway resistance, peripheral airway resistance, and airway reactivity assessed by methacholine aerosol challenge. The bronchial artery was perfused with autologous blood (control Qba = 0.6 ml.min-1.kg-1) in anesthetized ventilated sheep. The artery was perfused at either control (C) Qba or at high (H) Qba (300% of C Qba) for 3 h. Morphometry showed a doubling of the vascular area in airways exposed to H Qba (n = 4) compared with C Qba (n = 4). However, the significant increase in wall area could be accounted for only partially by the vascular changes, with edema fluid accumulation accounting for the major increase. Despite these changes, baseline airway resistance (n = 16) and peripheral airway resistance were both unaltered. Airway reactivity to methacholine before and after H Qba was also examined (n = 12). The 3 h of H Qba had no effect on airway reactivity regardless of whether challenge occurred with C or H Qba. The lack of effect of vascular engorgement on airway resistance or reactivity does not support a primary role for these factors in mediating airway obstruction.
Assuntos
Resistência das Vias Respiratórias/fisiologia , Brônquios/irrigação sanguínea , Fenômenos Fisiológicos Respiratórios , Sistema Respiratório/anatomia & histologia , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/fisiopatologia , Edema/induzido quimicamente , Edema/fisiopatologia , Masculino , Compostos de Metacolina/administração & dosagem , Compostos de Metacolina/farmacologia , Músculo Liso/anatomia & histologia , Músculo Liso/irrigação sanguínea , Músculo Liso/fisiologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Sistema Respiratório/fisiopatologia , OvinosRESUMO
Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83(2): 366-370, 1997.-Inflammatory changes and airway wall thickening are suggested to cause increased airway responsiveness in patients with asthma. In five sheep, the dose-response relationships of individual airways were measured at different lung volumes to methacholine (MCh) before and after wall thickening caused by the inflammatory mediator bradykinin via the bronchial artery. At 4 cmH2O transpulmonary pressure (Ptp), 5 microg/ml MCh constricted the airways to a maximum of 18 +/- 3%. At 30 cmH2O Ptp, MCh resulted in less constriction (to 31 +/- 5%). Bradykinin increased airway wall area at 4 and 30 cmH2O Ptp (159 +/- 6 and 152 +/- 4%, respectively; P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased airway luminal area (13 +/- 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH2O, postbradykinin, the maximal airway narrowing was not significantly different (26 +/- 5%; P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect on the MCh-induced airway constriction. We conclude that inflammatory fluid leakage in the airways cannot be a primary cause of airway hyperresponsiveness.
Assuntos
Pulmão/fisiopatologia , Edema Pulmonar/fisiopatologia , Respiração Artificial , Animais , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Medidas de Volume Pulmonar , Cloreto de Metacolina/farmacologia , Edema Pulmonar/diagnóstico por imagem , Ovinos , Tomografia Computadorizada por Raios XRESUMO
The lymphatic vessels of the lung provide an important route for clearance of interstitial edema fluid filtered from pulmonary blood vessels. However, the importance of lung lymphatics for the removal of airway liquid filtered from the systemic circulation of the lung has not been demonstrated. We studied the contribution of the bronchial vasculature to lung lymph flow in anesthetized, ventilated sheep (n = 35). With the bronchial artery cannulated and perfused (control flow = 0.6 ml. min-1. kg-1), lymph flow from the efferent duct of the caudal mediastinal lymph node was measured 1) during increased bronchial vascular perfusion (300% of control flow); 2) with a hydrated interstitium induced by a 1-h period of left atrial hypertension and subsequent recovery, both with and without bronchial perfusion; and 3) during infusion (directly into the bronchial artery) of bradykinin, an inflammatory mediator known to cause changes in bronchial vascular permeability. Increased bronchial perfusion for 90 min resulted in an average 35% increase in lung lymph flow. During left atrial hypertension, the increase in lung lymph flow was significantly greater with bronchial perfusion (339% increase over baseline) than without bronchial perfusion (138% increase). Furthermore, recovery after left atrial hypertension was more complete after 90 min without bronchial perfusion (91%) than with bronchial perfusion (63%). Infusion of bradykinin into the bronchial artery resulted in a prompt and prolonged 107% increase in lung lymph flow. This was not seen if the same dose was infused into the pulmonary artery. Thus bronchial vascular transudate contributes significantly to lymph flow from the efferent duct of the caudal mediastinal lymph node. These results demonstrate that lymph vessels clear excess fluid from the airway wall and should be considered when evaluating the effect of vascular leak in airway obstruction.
Assuntos
Artérias Brônquicas/fisiologia , Pulmão/fisiologia , Linfa/fisiologia , Animais , Velocidade do Fluxo Sanguíneo , Bradicinina/administração & dosagem , Brônquios/irrigação sanguínea , Pulmão/efeitos dos fármacos , Linfa/efeitos dos fármacos , Sistema Linfático/efeitos dos fármacos , Sistema Linfático/fisiologia , Circulação Pulmonar/fisiologia , Edema Pulmonar/fisiopatologia , OvinosRESUMO
Ventilation during ischemia attenuates ischemia-reperfusion lung injury, but the mechanism is unknown. Increasing tissue cyclic nucleotide levels has been shown to attenuate lung ischemia-reperfusion injury. We hypothesized that ventilation prevented increased pulmonary vascular permeability during ischemia by increasing lung cyclic nucleotide concentrations. To test this hypothesis, we measured vascular permeability and cGMP and cAMP concentrations in ischemic (75 min) sheep lungs that were ventilated (12 ml/kg tidal volume) or statically inflated with the same positive end-expiratory pressure (5 Torr). The reflection coefficient for albumin (sigmaalb) was 0.54 +/- 0.07 and 0.74 +/- 0. 02 (SE) in nonventilated and ventilated lungs, respectively (n = 5, P < 0.05). Filtration coefficients and capillary blood gas tensions were not different. The effect of ventilation was not mediated by cyclic compression of alveolar capillaries, because negative-pressure ventilation (n = 4) also was protective (sigmaalb = 0.78 +/- 0.09). The final cGMP concentration was less in nonventilated than in ventilated lungs (0.02 +/- 0.02 and 0.49 +/- 0. 18 nmol/g blood-free dry wt, respectively, n = 5, P < 0.05). cAMP concentrations were not different between groups or over time. Sodium nitroprusside increased cGMP (1.97 +/- 0.35 nmol/g blood-free dry wt) and sigmaalb (0.81 +/- 0.09) in nonventilated lungs (n = 5, P < 0.05). Isoproterenol increased cAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on sigmaalb. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester had no effect on lung cGMP (n = 9) or sigmaalb (n = 16) in ventilated lungs but did increase pulmonary vascular resistance threefold (P < 0.05) in perfused sheep lungs (n = 3). These results suggest that ventilation during ischemia prevented an increase in pulmonary vascular protein permeability, possibly through maintenance of lung cGMP by a nitric oxide-independent mechanism.
Assuntos
Permeabilidade Capilar/fisiologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Pulmão/metabolismo , Respiração Artificial , Animais , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Isquemia/metabolismo , Isquemia/fisiopatologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/farmacologia , Circulação Pulmonar/fisiologia , Ovinos , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
We studied the effects of increased airway pressure caused by increasing levels of positive end-expiratory pressure (PEEP) on bronchial arterial pressure-flow relationships. In eight alpha-chloralose-anesthetized mechanically ventilated sheep (23-27 kg), the common bronchial artery, the bronchial branch of the bronchoesophageal artery, was cannulated and perfused with a pump. The control bronchial blood flow (avg 12 +/- 1 ml/min or 0.48 ml X min-1 X kg-1) was set to maintain mean bronchial arterial pressure equal to systemic blood pressure. Pressure-flow curves of the bronchial circulation were measured by making step changes in bronchial blood flow, and changes in these curves were analyzed with measurements of the pressure at zero flow and the slope of the linearized curve. The zero-flow pressure represents the effective downstream pressure, and the slope represents the resistance through the bronchial vasculature. At a constant bronchial arterial pressure of 100 mmHg, an 8 mmHg increase in mean airway pressure caused a 40% reduction in bronchial blood flow. Under constant flow conditions, increases in mean airway pressure with the application of PEEP caused substantial increases in bronchial arterial pressure, averaging 4.6 mmHg for every millimeters of mercury increase in mean airway pressure. However, bronchial arterial pressure at zero flow increased approximately one-for-one with increases in mean airway pressure. Thus the acute sensitivity of the bronchial artery to changes in mean airway pressure results primarily from changes in bronchovascular resistance and not downstream pressure.