Effect of hypoxia on respiratory system impedance in dogs.

The effects of hypoxia on lung and airway mechanics remain controversial, possibly because of the confounding effects of competing reflexes caused by systemic hypoxemia. We compared the effects of systemic hypoxemia with those of unilateral alveolar hypoxia (with systemic normoxemia) on unilateral respiratory system impedance (Z) in intact, anesthetized dogs. Independent lung ventilation was obtained with a Kottmeier endobronchial tube. Individual left and right respiratory system Z was measured during sinusoidal forcing with 45 ml of volume at frequencies of 0.2-2.1 Hz during control [100% inspired O2 fraction (FIO2)], systemic hypoxemia (10% FIO2), and unilateral alveolar hypoxia (0% FIO2 to left lung, 100% FIO2 to right lung). During systemic hypoxemia, there was a mean Z magnitude increase of 18%. This change was entirely attributable to a decrease in the imaginary component of Z; there was no change in the real component of Z. Administration of atropine (0.2 mg/kg) did not block the increase in Z with systemic hypoxemia. In contrast, there was no change in Z in the lung subjected to unilateral alveolar hypoxia. We conclude that alveolar hypoxia has no direct effect on lung mechanical properties in intact dogs. In contrast, systemic hypoxemia does increase lung impedance, apparently through a noncholinergic mechanism.

Species differences in pulmonary vasoactive responses to histamine, 5-hydroxytryptamine, and KCl.

Species differences in the longitudinal distribution of pulmonary vascular resistance (PVR) in response to 5-hydroxytryptamine (5-HT) or histamine (His) may be attributed to variations in the distribution of functional smooth muscle between arteries and veins estimated by the response to KCl. Isolated dog, guinea pig, or rabbit lungs were perfused at a constant flow = 55-75 ml.min-1.kg body wt-1. Pulmonary arterial (Ppa); arterial, double, and venous occlusion (Po,a; Pdo; Po,v, respectively); and pulmonary venous (Ppv) pressures were measured before and after increasing PVR by infusing His, 5-HT, or KCl. 5-HT and His increased Ppa--Pdo in rabbits but Pdo--Ppv in guinea pigs. In dogs, 5-HT increased Ppa--Po,a, but His increased Pdo--Ppv. Dynamic (Co,v) and static vascular compliance (CP-Q), as well as critical closing pressure (Pcc, the gamma-intercept of pressure-flow curves), were also measured. At baseline, Co,v was the same among species. However, CP-Q was higher than Co,v in all lungs and was significantly different among species in order of (in ml.cmH2O-1.100 g-1) rabbit (4.54 +/- 0.28) > guinea pig (3.31 +/- 0.18) > dog (2.21 +/- 0.13). Increases in Pcc correlated with increases in microvascular resistance (Po,a--Po,v) but not with increases in PVR after agonist infusion. KCl responses suggest that guinea pigs and rabbits have relatively more functional smooth muscle in venous and arterial microvessels, respectively, whereas dogs have approximately equal amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclooxygenase inhibition prevents PMA-induced increase in pulmonary vascular permeability to albumin.

In a previous study, we demonstrated that phorbol myristate acetate-(PMA) induced injury in isolated blood-perfused rabbit lungs was characterized by increased pulmonary vascular resistance (PVR) and permeability to water as measured by fluid filtration coefficient (Kf). The Kf increase was prevented by pretreatment with three cyclooxygenase inhibitors, indomethacin, ibuprofen, and meclofenamate. Other studies have shown that PMA causes a decrease in pulmonary vascular surface area, probably due to the increase in arterial resistance. Measurement of Kf requires increased microvascular pressure, and therefore Kf estimates the permeability of the entire vascular bed. Thus the permeability of the flowing vessels may be overestimated by Kf. In this study, we chose to investigate the effect of PMA on vascular permeability to protein by measuring albumin leak. Because this measurement does not require a hydraulic stress, it is more likely to reflect the permeability of flowing vessels. PMA administration (5 x 10(-8) M) caused significant increases in both PVR and 125I-labeled bovine serum albumin leak. Cyclooxygenase inhibition with indomethacin, ibuprofen, or meclofenamate prevented the PMA-induced increase in albumin leak without affecting the PVR increase. These results suggest that cyclooxygenase-mediated products of arachidonic acid mediate the PMA-induced increase in vascular permeability to both water and protein.

Bronchoalveolar eosinophilia in random-source versus purpose-bred dogs.

Eosinophils (EOS) have been implicated in changes in airway and vascular reactivity in a variety of disease states. Analysis of cells in bronchoalveolar lavage samples from chronic, heartworm-free random-source (RS) dogs indicated higher leukocyte counts with markedly higher percent and total numbers of EOS than were present in purpose-bred (PB) animals. Bronchoalveolar lavage fluid (BALF) obtained from RS dogs had a significantly elevated total nucleated cell count: 0.8 x 10(6) vs 0.4 x 10(6) for the PB dogs. RS dogs had 24% +/- 5% and PB dogs had 3% +/- 0.7% EOS. The RS animals with elevated EOS had similar percentages of neutrophils: 4% +/- 0.6% as the PB animals. Despite aggressive anthelminthic treatment, the abnormal BALF cellular profile of the RS animals persisted even though circulating levels of EOS in this group decreased. Analysis of BALF for thromboxane B2 (TxB2) and 6-keto-prostaglandin F1(1a) (6-keto-PGF1a) indicated that only the TxB2 levels were significantly different between groups. The RS BALF TxB2 levels were 73 +/- 14 pg/ml vs 23 +/- 3 pg/ml for the PB group (P < 0.05). Regression analysis of the relationship between increasing TxB2 levels and the absolute number of EOS per milliliter of BALF obtained from the RS dogs indicated a significant correlation (r = 0.83, P < 0.0001). No difference in plasma levels of these mediators was observed. Other physiologic parameters also differed between the two groups: the RS group had significantly increased heart rates and cardiac output under baseline conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine prevents phorbol ester injury in rabbit lungs: role of leukotrienes and TNF.

The objective of this study was to determine whether adenosine (ADO) prevents phorbol myristate acetate- (PMA) induced lung injury by modulating peptidoleukotrienes (LT) and/or tumor necrosis factor (TNF) production. PMA significantly increased pulmonary vascular resistance (PVR, 275 +/- 4 to 447 +/- 30 cmH2O.1-1.min) and microvascular filtration coefficient.(Kf, 0.024 +/- 0.002 to 0.040 +/- 0.006 g.min-1.cmH2O-1) in isolated blood-perfused rabbit lungs. ADO (5 mumol/min) blocked the increases in PVR (257 +/- 9 to 283 +/- 26) and Kf (0.028 +/- 0.005 to 0.018 +/- 0.002). After PMA (30 min), perfusate levels of LTC4 + LTD4 increased by 15.3 +/- 2.1 pg/ml; LTE4 increased by 15.1 +/- 4.1 pg/ml. ADO reduced the increase in LTC4 + LTD4 to 2.7 +/- 6.1 pg/ml, but total LT increased by 31.9 +/- 16.6 pg/ml, implying that ADO enhanced the conversion of LTC4 and LTD4 to LTE4. MK-886 (L663,536), an LT synthesis inhibitor, blocked the increase in total LT (6.1 +/- 13.9 pg/ml) but did not reduce the PMA-induced increase in Kf (0.022 +/- 0.003 to 0.035 +/- 0.005) or PVR (238 +/- 11 to 495 +/- 21). After PMA administration, perfusate TNF levels were not different from the 10-fold increase observed in control experiments and were not reduced by ADO or MK-886. TNF production was independent of perfusate blood components and presumably due to low levels of endotoxin in the perfusate (70-90 ng/ml). These results indicate that ADO does not protect against PMA-induced acute lung injury by altering circulating levels of LT or TNF.

Vascular resistance and Kf in normal and PMA-injured rabbit lungs: effects of adenosine.

The effects of adenosine (ADO) on pulmonary vascular resistance (PVR) distribution, vascular compliance (C), and permeability were determined in normal and PMA-injured isolated rabbit lungs perfused with a 1:1 mixture of 6% albumin in Krebs-Henseleit buffer and autologous blood. ADO or vehicle was continuously infused into the reservoir at 1,4, or 5 mumol/min after a 1-mumol bolus of ADO or vehicle. The capillary filtration coefficient (Kf) and arterial, venous, and double occlusion pressures were measured at baseline and 30 min after phorbol myristate acetate (PMA; 4 x 10(-8) M) or vehicle. Perfusate differential and total leukocyte counts as well as adenine nucleotides, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) concentrations were determined at each measurement period. ADO was recovered as hypoxanthine and inosine in the perfusate. ADO alone did not alter PVR, C, Kf, or TxB2 but reduced 6-keto-PGF1 alpha levels. PMA induced an increase in Kf (0.024 +/- 0.002 to 0.040 +/- 0.006 g.cmH2O-1.min-1, P less than 0.05) that was completely blocked by 4 or 5 mumol/min ADO. PVR increased by 63 +/- 11% after PMA, primarily in the arteries and arterial and venous microvessels. The postcapillary resistance increase was blunted by 4 mumol/min ADO; 5 mumol/min ADO prevented the PVR increase in all segments. ADO did not affect the initial adherence of neutrophils in the lung or the PMA-induced 87 +/- 2% decrease in circulating leukocytes (greater than 98% lymphocytes) or threefold increase in TxB2 levels. These results suggest that protection by ADO is not mediated by the altering of cyclooxygenase products or by leukocyte adherence.

Cyclooxygenase inhibitors prevent ethchlorvynol-induced injury in rat and rabbit lungs.

The effect of three chemically dissimilar cyclooxygenase inhibitors on ethchlorvynol-(ECV) induced acute lung injury was studied in isolated buffer-perfused rat and blood-perfused rabbit lungs. ECV caused the microvascular fluid filtration coefficient (Kf) to increase by greater than threefold in the rat lungs and twofold in the rabbit lungs. ECV caused increased pulmonary vascular resistance (PVR) and microvascular pressure measured by the double occlusion technique (Pdo) compared with the vehicle control group in the rat experiments. However, ECV had no effect on PVR or Pdo in the rabbit experiments. Pretreatment with the cyclooxygenase inhibitors indomethacin, ibuprofen, and meclofenamate prevented the increase in microvascular permeability in both the rat and rabbit lung preparations. The cyclooxygenase inhibitors also prevented the ECV-induced PVR and Pdo increases in the rat lungs but had no effect on PVR or Pdo in the rabbit lungs. These results indicate that cyclooxygenase products of arachidonate metabolism mediate the ECV-induced Kf increase in both isolated rat and rabbit lungs.

Cyclooxygenase inhibition prevents PMA-induced increases in lung vascular permeability.

The effect of cyclooxygenase inhibition in phorbol myristate acetate (PMA)-induced acute lung injury was studied in isolated constant-flow blood-perfused rabbit lungs. PMA caused a 51% increase in pulmonary arterial pressure (localized in the arterial and middle segments as measured by vascular occlusion pressures), a 71% increase in microvascular permeability (measured by the microvascular fluid filtration coefficient, Kf), and a nearly threefold increase in perfusate thromboxane (Tx) B2 levels. Cyclooxygenase inhibition with three chemically dissimilar inhibitors, indomethacin (10(-7) and 10(-6) M), meclofenamate (10(-6) M), and ibuprofen (10(-5) M), prevented the Kf increase without affecting the pulmonary arterial pressure increase or resistance distribution changes after PMA administration. The specific role of TxA2 was investigated by pretreatment with OKY-046, a specific Tx synthase inhibitor, or infusion of SQ 29548, a TxA2 receptor antagonist; both compounds failed to protect against either the PMA-induced permeability or the vascular resistance increase. These results indicate that cyclooxygenase-mediated products of arachidonic acid other than TxA2 mediate the PMA-induced permeability increase but not the hypertension.