Assessment of therapy of upper airway obstruction.

Five patients with fixed upper airway obstruction were evaluated with maximum expiratory and inspiratory flow-volume curves before and after surgical repair of the obstruction. Flow-volume curves improved notably in two patients, improved moderately in two, and deteriorated in one. Symptoms and direct visualization of the obstruction before and after surgery correlated well with the changes seen in the flow-volume curves. None of the peak expiratory flow rates returned to predicted values after surgery, indicating at least some residual obstruction in all patients. It is concluded that flow-volume curves are an accurate, noninvasive technique for the diagnosis and subsequent assessment of therapy in patients with fixed upper airway obstruction.

The clinical assessment of roentgenographically atypical pulmonary sarcoidosis.

We studied 89 patients in whom the clinical diagnosis of sarcoidosis was supported by the findings on tissue biopsy. A chest roentgenogram in 14 of the patients showed one of the following atypical features: large pulmonary nodules, an alveolar parenchymal pattern or a pleural effusion. Diagnoses of infection, malignancy or vasculitis were suggested by interpretations of atypical chest roentgenograms in eight of these 14 patients. Nonspecific and misleading clinical information contributed. The diagnosis of sarcoidosis was corroborated by extrathoracic tissue biopsies in 11 of the 14 patients. Over an average observation period of 38 months, the 14 patients remained classified as having sarcoidosis. This suggests that an extrathoracic tissue biopsy, whose findings are consistent with sarcoidosis, is often sufficient to support a clinical diagnosis of some forms of roentgenographically atypical pulmonary sarcoidosis.

Respiratory patterns associated with hemoglobin desaturation during sleep in chronic obstructive pulmonary disease.

Respiration during sleep was monitored in ten patients with chronic obstructive pulmonary disease (COPD) and related to measures of hemoglobin saturation and intrathoracic pressure (ITP) or abdominal wall movement. Seven of the ten patients showed episodic hemoglobin desaturation of at least 5 percent during sleep. Two distinct patient groups could be distinguished on the basis of ITP measurements and breathing patterns. Desaturation was associated with reduced negative ITP or respiratory movement in three patients and with increased negative ITP or respiratory movement in four patients. These data suggest that desaturation may result from at least two distinct mechanisms, involving reduced respiratory effort in one group and increased upper airway occlusion in the other. Desaturation associated with reduced respiratory effort was primarily REM-sleep related and consisted of a few sustained episodes. Desaturation episodes associated with upper airway occlusion occurred in all stages of sleep and were very frequent and of short duration.

Edema from cyclooxygenase products of endogenous arachidonic acid in isolated lung.

We infused A23187, a calcium ionophore, into the pulmonary circulation of dextran-salt-perfused isolated rabbit lungs to release endogenous arachidonic acid. This led to elevations in pulmonary arterial pressure and to pulmonary edema as measured by extravascular wet-to-dry weight ratios. The increase in pressure and edema was prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and by 1-benzylimidazole, a selective inhibitor of thromboxane (Tx) A2 synthesis. Transvascular flux of 125I-albumin from vascular to extravascular spaces of the lung was not elevated by A23187 but was elevated by infusion of oleic acid, an agent known to produce permeability pulmonary edema. We confirmed that A23187 leads to elevations in cyclooxygenase products and that indomethacin and 1-benzylimidazole inhibit synthesis of all cyclooxygenase products and TxA2, respectively, by measuring perfusate levels of prostaglandin (PG) I2 as 6-ketoprostaglandin F1 alpha, PGE2, and PGF2 alpha and TxA2 as TxB2. We conclude that release of endogenous pulmonary arachidonic acid can lead to pulmonary edema from conversion of such arachidonic acid to cyclooxygenase products, most notably TxA2. This edema was most likely from a net hydrostatic accumulation of extravascular lung water with an unchanged permeability of the vascular space, since an index of permeability-surface area product (i.e., transvascular albumin flux) was not increased.

Severe sarcoidosis in pregnancy.

A case of pulmonary sarcoidosis in a pregnant woman with severe constitutional symptoms and markedly restricted pulmonary function is presented. Serial pulmonary function testing before and during steroid therapy documented significant improvement. Although the severity of this patient's disease is apparently rare, more studies are required to define the prevalence of significant pulmonary function impairment in pregnant women with sarcoidosis.

Inhibition of eicosanoids does not prevent neutrophil injury from phorbol in isolated rabbit lung.

Studies suggest that pulmonary and neutrophil cyclooxygenase and lipoxygenase products (i.e., eicosanoids) play a role in oxidant lung injury. We tested the hypothesis that such eicosanoids contribute to lung injury from activation of rabbit neutrophils by phorbol myristate acetate (PMA) in the pulmonary circulation of salt-perfused isolated rabbit lung preparations. We measured lung injury from PMA-activated neutrophils under zone 2 pulmonary vascular conditions with transvascular albumin flux by 125I-labeled albumin. We found that this flux was increased; catalase prevented the increase, confirming that the increase was from oxidant injury. However, results were inconsistent: about one-half of the preparations showed a marked increase and about one-half were not elevated. In preparations with a > 40-mmHg increase in pulmonary arterial pressure (Ppa), albumin flux increased, and in those with Ppa < 40 mmHg it did not. In those with Ppa > 40 mmHg, vascular volume, and presumably vascular surface area, was markedly reduced. We next studied PMA-activated neutrophils under zone 3 pulmonary vascular conditions in preparations with Ppa that increased < 40 mmHg. Albumin flux or filtration coefficient (Kf,c) was used to measure injury. Both were elevated. As with albumin flux, catalase prevented increases in Kf,c. BW-755C (a dual lipoxygenase and cyclooxygenase inhibitor) prevented increases in cyclooxygenase products and leukotriene B4 (a lipoxygenase product) but did not prevent increases in Kf,c. We conclude that a marked decrease in vascular volume can occur in zone 2 preparations and may mask the presence of injury as measured by transvascular albumin flux. A zone 3 vascular condition overcomes the vasoconstrictor-induced decrease in surface area and unmasks injury. Finally, oxidant injury from PMA-stimulated rabbit neutrophils in isolated rabbit lungs cannot be readily attributed to formation of eicosanoids.

cAMP levels from endogenous and exogenous arachidonic acid in isolated dog lung.

We infused exogenous arachidonic acid (AA) into salt-perfused isolated dog lungs. This led to elevations in adenosine 3',5'-cyclic monophosphate (cAMP) which were from conversion of the AA to cyclooxygenase products. The maximal levels of cAMP occurred at far less than maximal levels of cyclooxygenase products. Next, we infused A 23187 to release endogenous pulmonary AA. This led to elevations in cAMP that were from conversion of this endogenous AA to cyclooxygenase products. The level of these products was far less than maximal levels from exogenous AA. However, maximal levels of cAMP from conversion of endogenous AA were similar to maximal levels of cAMP from conversion of exogenous AA. We conclude that maximal levels of pulmonary cAMP from endogenous or exogenous AA are from conversion of the AA to far less than maximal levels of pulmonary cyclooxygenase products. This indicates that levels of cAMP rather than levels of cyclooxygenase products are a potential rate-limiting step in cAMP-linked pulmonary actions of such products from pulmonary conversion of endogenous or exogenous AA.

Distribution of cyclooxygenase products with cyclooxygenase inhibition in isolated dog lung.

Arachidonic acid metabolism can lead to synthesis of cyclooxygenase products in the lung as indicated by measurement of such products in the perfusate of isolated lungs perfused with a salt solution. However, a reduction in levels of cyclooxygenase products in the perfusate may not accurately reflect the inhibition of levels of such products as measured in lung parenchyma. We infused sodium arachidonate into the pulmonary circulation of isolated dog lungs perfused with a salt solution and measured parenchymal, as well as perfusate, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2), and thromboxane B2 (TxB2). These studies were repeated with indomethacin (a cyclooxygenase enzyme inhibitor) in the perfusate. We found that indomethacin leads to a marked reduction in perfusate levels of PGF2 alpha, PGE2, 6-keto-PGF1 alpha, and TxB2, as well as a marked reduction in parenchymal levels of 6-keto-PGF1 alpha and TxB2 when parenchymal levels of PGF2 alpha and PGE2 are not reduced. We conclude that, with some cyclooxygenase products, a reduction in levels of these products in the perfusate of isolated lungs may not indicate inhibition of levels of these products in the lung parenchyma and that a reduction in one parenchymal product may not predict the reduction of other parenchymal products. It can be speculated that some of the physiological actions of indomethacin in isolated lungs may result from incomplete or selective inhibition of synthesis of pulmonary cyclooxygenase products.

The effects of neutrophils and phospholipase A2 on transvascular albumin flux in isolated rabbit lungs.

In this study, addition of phospholipase A2 (PLA2) to salt-perfused isolated rabbit lungs containing rabbit polymorphonuclear leukocytes leads to an increase in pulmonary capillary permeability. We add 1.5 X 10(8) polymorphonuclear leukocytes to the perfusate. Next, indomethacin is added to the perfusate and 40 units of PLA2 are infused into the pulmonary arterial inflow of the lungs. At the end of the study, a lung sample is removed for measurement of transvascular albumin flux using I125-albumin as a measure of the permeability-surface area product. Control studies demonstrate no increase in transvascular albumin flux. Addition of a dual cyclooxygenase and lipoxygenase inhibitor, BW755C, to the perfusate prevents the increase in transvascular albumin flux. We conclude that PLA2 interacts with polymorphonuclear leukocytes to increase protein permeability. Since PLA2 can release endogenous arachidonic acid and platelet-activating factor from cells, this suggests that release of such products may contribute to an increase in pulmonary capillary permeability from polymorphonuclear leukocytes. The ability of BW755C to prevent the increase suggests the possibility that lipoxygenase products contribute.

Lymphocyte beta-adrenergic refractoriness induced by theophylline or metaproterenol in healthy and asthmatic subjects.

Beta-adrenergic refractoriness was assessed in human lymphocytes following in vivo administration of the beta-adrenergic agonist, metaproterenol, the phosphodiesterase inhibitor, theophylline, or both concomitantly, to normal and asthmatic subjects. In normal subjects both beta-adrenergic receptor number and isoproterenol stimulated cAMP response decreases during therapy with metaproterenol (59 +/- 3; 51 +/- 16% of control, respectively), theophylline (76 +/- 6; 78 +/- 16), or concomitant metaproterenol and theophylline (47 +/- 4; 69 +/- 13). The asthmatic subjects were of two types; one type responding to metaproterenol or theophylline therapy by down regulation of receptor number to zero or near zero values, and a second group of asthmatics insensitive to down regulation of receptor number. The results suggest that the induction of the refractory state is different between asthmatics and non-asthmatics, and that there may be a role for cAMP in the development of beta-adrenergic refractoriness, in vivo.

Cyclooxygenase products from endogenous arachidonic acid in isolated dog and rabbit lungs.

We infused various doses of A23187, a calcium ionophore, into the pulmonary circulation to release endogenous arachidonic acid (AA) in salt-perfused isolated dog and rabbit lungs. Levels of prostaglandin (PG) I2 (as 6-keto-PGF1 alpha), thromboxane A2 (TXA2) as TXB2, and PGF2 alpha but not levels of PGE2 were elevated. Levels of TXA2 were similar between dog and rabbit lungs but levels of PGI2 and PGF2 alpha were higher in dog than in rabbit lungs. However, this difference was not the same at all levels of TXA2. At lower levels of TXA2, the differences were greater and narrowed at higher levels of TXA2. This led to an overlap in the ratios of PGI2/TXA2 and PGF2 alpha/TXA2 between dog and rabbit lungs. We conclude that species differences exist in formation of cyclooxygenase products between dog and rabbit lungs. With respect to products, differences may be dependent on the level of products in response to an AA-releasing agent. This suggests that rabbit lungs can be more sensitive than dog lungs to formation of relatively greater amounts of TXA2. However, the ratios of PGI2/TXA2 and PGF2 alpha/TXA2 can be similar between these species as follows: (1) if there is a sufficient dose of AA-releasing stimulus, or (2) if there is a sufficient difference in doses of the stimulus, with the lower dose being applied to rabbit lungs. Speculatively, physiologic effects of cyclooxygenase products may be similar under these conditions despite the species differences.

Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs.

Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of A23187, exogenous phospholipase A2 and exogenous arachidonic acid on pulmonary vascular resistance in isolated rabbit lung.

The authors gave infusions of exogenous arachidonic acid (AA), exogenous phospholipase A2 (PLA2) or A23187 into the pulmonary circulation of isolated salt-perfused rabbit lungs. Exogenous PLA2 and A23187 are agents that release the AA that is usually in the lung (i.e., endogenous pulmonary AA). The exogenous AA or A23187 led to pulmonary cyclooxygenase enzyme conversion of exogenous and endogenous AA to thromboxane A2 (TXA2), as TXB2, and prostacyclin, as 6-keto-prostaglandin-F1 alpha, as well as to elevations in pulmonary vascular resistance (PVR). The elevations in PVR as well as the elevations in TXB2 and 6-keto-prostaglandin-F1 alpha were prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and the elevations in TXB2 and PVR but not the elevations in 6-keto-prostaglandin-F1 alpha were prevented by 1-benzylimidazole, a selective inhibitor of thromboxane synthesis. Maximum elevations in PVR occurred from conversion of AA to less than maximum levels of TXA2. Exogenous PLA2 led to release of endogenous AA with conversion to prostacyclin. However, such release of endogenous AA by exogenous PLA2 did not lead to conversion to TXA2 or to elevations in PVR. The authors conclude that elevations in PVR that depend on conversion of AA to TXA2 are limited by factors other than the amount of TXA2 or the amount of AA that is potentially available for such conversion.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of cyclooxygenase production does not prevent arachidonate from increasing extravascular lung water and albumin in an isolated dog lung.

We examined the hypothesis that arachidonic acid can lead to pulmonary edema, increased pulmonary vascular permeability, and increased pulmonary vascular resistance (PVR) in an isolated dog lung. The lung was perfused with a dextran-salt solution to remove blood elements. Compared to controls, 20 mg/min sodium arachidonate into the pulmonary circulation led to edema and to an increase in a permeability and surface area index (PSI%), PVR, and cyclooxygenase (i.e. prostaglandin) production as measured by 6-keto-PGF1 alpha, TXB2 and PGF2 alpha. With 20 mg/min arachidonate, indomethacin inhibited the increase in cyclooxygenase production, reduced the increase in PVR and increased the edema and PSI%. Indomethacin, alone, did not produce edema or an increase in PSI% or PVR. Lower doses of arachidonate (0.1 to 5 mg/min) led to increasing cyclooxygenase production without obvious edema or an increase in PSI% or PVR. We conclude: 1) arachidonate can lead to pulmonary edema and an increase in PVR, and may lead to an increase in pulmonary vascular permeability; these effects of arachidonate do not require normal numbers of circulating blood elements; 2) arachidonate appears to contribute to pulmonary edema and increased PSI% by a noncyclooxygenase effect since inhibition of cyclooxygenase production did not prevent, and lower doses of cyclooxygenase production did not produce edema or an increase in PSI%; 3) the increase in PVR appeared to have a cyclooxygenase component since inhibition of cyclooxygenase production reduced the increase, and 4) indomethacin can increase the magnitude of edema and PSI% from arachidonate by an undefined mechanism.

Modification of induced airway constriction in healthy subjects.

Unlike asthmatics, healthy persons are relatively unresponsive to airway constrictors. By using partial expiratory flow-volume (PEFV) curves the authors have demontrated, in healthy subjects, dose-related decreases in flow rates following challenge with histamine and methacholine aerosols. With the use of semilogarithmic dose-response curves they have shown that 80 mg oral propranolol augmented, whereas oral pretreatment with 400 mg W10294A (an experimental bronchodilator) decreased, histamine and methacholine-induced airway constriction. However, 300 mg of orally administered aminophylline failed to modify the airway constrictor effects of histamine and methacholine. Moreover, variation was noted in induced airway constriction in healthy subjects with decreases in flow rates being greater in the morning than in the afternoon. The authors conclude that (1) propranolol augments whereas theophylline fails to prevent nonspecific induced airway constriction in healthy subjects. This suggests that the bronchodilator action of theophylline may be unrelated to its phosphodiesterase inhibitory activity, (2) control of volume history, by use of partial expiratory flow-volume curves, is useful in quantifying pharmacologic protection and augmentation of nonspecific induced airway constriction in healthy subjects and (3) conclusions resulting from observations of induced airway constriction in healthy subjects may be dependent upon the effects of diurnal variation.

Determinants of oxygen desaturation in the course of ventilation during sleep in chronic obstructive pulmonary disease.

During sleep, none of 9 subjects with chronic obstructive pulmonary disease (COPD) were apneic. Despite ventilation, acute arterial oxygen desaturation of 11% or more occurred in 6 of them. The other 3 were nondesaturators (i.e., 3% or less desaturation) during sleep. The desaturation that occurred in the 6 subjects with COPD was associated with episodes of (1) esophageal pressure or abdominal respiratory movement that acutely decreased in amplitude during rapid-eye-movement (REM) sleep, or (2) esophageal pressure or abdominal respiratory movement that acutely increased in amplitude in association with snoring during non-REM and REM sleep. During daytime wakefulness, ventilatory responses to hypoxia and hypercapnia were markedly less in the 6 desaturators compared with the 3 nondesaturators and 5 healthy control subjects. The decreased ventilatory responses in the 6 desaturators appeared to result from both impaired respiratory mechanical effectiveness and impaired respiratory center responsiveness to chemoreceptor stimulation. We suggest that subjects with COPD with these respiratory impairments are predisposed to develop severe nonapneic oxygen desaturation during the added respiratory impairment of REM sleep or of what appears to be sleep-related partial upper airway obstruction.