Prognostic Significance of Pulmonary Artery to Aorta Ratio and Other CT Markers in Pulmonary Fibrosis With and Without Emphysema.

Pulmonary hypertension (PH) is associated with decreased survival in patients with pulmonary fibrosis and combined pulmonary fibrosis and emphysema. Main pulmonary artery (PA) diameter and PA diameter/ascending aortic diameter (PA/AA) ratio, as measured on CT, have recently emerged as specific markers for PH. Our single-center retrospective study found that PA/AA ratio > 1 is associated with decreased survival in individuals with pulmonary fibrosis, with or without emphysema. Our study also describes markers of cardiac remodeling, and the echocardiographic diagnosis of PH in this patient population.

Primary pulmonary hypertension in the elderly.

Primary pulmonary hypertension is usually considered a disease of younger adults. We reviewed the natural course of primary pulmonary hypertension in patients aged 65 years or greater. During an 8-year period, 63 elderly patients were discharged from our hospital with a diagnosis of pulmonary hypertension. In eight instances, an elevated mean pulmonary arterial pressure (greater than 25 mm Hg) could not be explained by secondary causes. These elderly patients with primary pulmonary hypertension had symptoms common to younger patients with this disease, including dyspnea (eight patients), chest pain (five), pedal edema (four), and fatigue (one). In all but one patient, the initial diagnosis was incorrect, and the patients were thought to have more common diseases of the elderly that cause similar symptoms. Coexisting medical problems were common and further obscured the correct diagnosis. Survival was significantly shorter in those patients with symptoms of less than 6 months' duration. Primary pulmonary hypertension should be considered in the differential diagnosis in elderly patients with unexplained dyspnea and chest pain.

A simple assay for ecto-5'-nucleotidase using intact pulmonary artery endothelial cells. Effect of endotoxin-induced cell injury.

Adenosine may be protective in acute vascular injury by inhibiting platelet aggregation and neutrophil oxidant release. In contrast, adenine nucleotides, which may be released with acute vascular injury, stimulate platelet aggregation and neutrophil oxidant release. Ectonucleotidases, membrane enzymes that catabolize extracellular nucleotides, are the primary mechanism for degrading circulating nucleotides to adenosine. Ecto-5'-nucleotidase converts extracellular AMP to adenosine. We hypothesized that endothelial cell injury alters ecto-5'-nucleotidase activity. Using a novel assay first reported by Jamal et al. (Biochem J 250: 369-373, 1988) with rat adipocytes, we studied the properties of ecto-5'-nucleotidase in intact monolayers of cultured bovine pulmonary artery endothelial cells (BPAEC) and examined the effect of endotoxin on enzyme activity. The assay uses a fluorescent analog of AMP, 1,N6-etheno-AMP (E-AMP), as the substrate for ecto-5'-nucleotidase, and measures ethenoadenosine (E-Ado) formation. Etheno-AMP in Hepes buffer, pH 7.4, at 22 degrees, was added to confluent monolayers of BPAEC; samples of supernatant were collected after various intervals, and E-AMP and E-Ado were quantitated by HPLC. Using these methods we found a Km of 15 +/- 6 microM, a pH optimum of 7.48, minimal effect of MgCl2 or CaCl2 at physiologic pH, and inhibition by alpha,beta-methylene ADP, a known 5'-nucleotidase inhibitor. We established that the monolayer assay was indeed measuring cell surface associated 5'-nucleotidase. To determine the effect of endotoxin, we incubated confluent monolayers with endotoxin in Minimal Essential Medium plus 10% fetal bovine serum for 24 hr, washed them, and assessed the conversion of E-AMP to E-Ado by the endotoxin-injured cells. Endotoxin stimulated endothelial ecto-5'-nucleotidase activity. This increase in 5'-nucleotidase activity in response to endotoxin injury may represent an important clearance mechanism for circulating adenine nucleotides and may be protective in acute vascular injury by increasing adenosine production.

Platelet-activating factor (PAF)-induced platelet aggregation. Modulation by plasma adenosine and methylxanthines.

This study examined the role of plasma adenosine in the modulation of platelet-activating factor (PAF) activity on platelet aggregation and serotonin (5-HT) release in human platelet-rich plasma (PRP). In addition, the effects of methylxanthines (e.g. theophylline and caffeine) were studied on PAF-induced platelet aggregation in PRP isolated from blood samples from healthy subjects. Also, PAF-induced platelet aggregation was examined in PRP samples of patients receiving theophylline treatment. These studies demonstrate that plasma adenosine levels (0.1 to 0.3 microM) play a key role in negative modulation of PAF activity on platelet aggregation and 5-HT release. After depletion of plasma adenosine, the platelet-aggregating activity of PAF was increased greatly (> 10-fold). PAF at concentrations of 0.1 to 12 microM caused no 5-HT release in PRP containing normal amounts of adenosine (blood collected in the presence of 2'-deoxycoformycin and dilazep), whereas PAF at 0.1 microM caused 5-HT release (45%) in adenosine-depleted PRP, demonstrating that plasma adenosine is much more inhibitory of 5-HT release than platelet aggregation. The adenosine antagonists theophylline (50 microM), caffeine (50 microM) and a xanthine derivative, 3,7-dimethyl-l-propargylxanthine (DMPX, 10 microM) (a more specific adenosine A2 receptor antagonist), potentiated PAF activity on platelet aggregation in PRP samples containing adenosine. Also, patients receiving theophylline treatments showed significantly greater platelet aggregation induced by PAF in their PRP samples. PAF induced a rapid increase (80% in 15 sec) in intracellular Ca2+ mobilization, which was strongly inhibited by adenosine (IC50, 0.3 microM). Our studies suggest that agents that can increase plasma adenosine levels (e.g. inhibitors of adenosine uptake and adenosine metabolism) or methylxanthines may be useful in altering (inhibiting or enhancing, respectively) PAF actions on platelets and other tissues.

Pulmonary hypertensive diseases.

Pulmonary hypertension may occur as a primary disorder of the pulmonary vasculature or secondary to a variety of cardiac or pulmonary diseases. The reversibility of pulmonary hypertension is dependent on the relative contribution of reversible vasoconstriction and irreversible structural changes in the pulmonary vessels. Despite recent advances in the understanding of pulmonary vascular physiology, knowledge of the pathogenesis and natural history of pulmonary hypertension has been limited by an inability to measure pulmonary arterial pressure noninvasively. Thus, when patients have symptoms or signs of pulmonary hypertension, the disease is usually at an advanced stage. It is possible that early in the course of hypoxic pulmonary disease, pulmonary hypertension may be protective in optimizing matching of ventilation and perfusion. It is not known at what point pulmonary hypertension per se becomes harmful. Certainly, treatment directed at underlying cardiac or pulmonary disease is indicated. It also seems reasonable to treat severe degrees of pulmonary hypertension complicated by right ventricular dysfunction. With the advent of orally effective pulmonary vasodilators, direct treatment of primary and secondary pulmonary hypertension may now be possible. Hopefully, with careful clinical evaluation of the response to vasodilator therapy, we will learn whether these drugs prolong life and reduce morbidity in primary and secondary pulmonary hypertension. In the meantime, much more information is needed regarding the mechanisms of acute pulmonary vasoconstriction and sustained pulmonary hypertension. In addition, a means of early identification of patients with mild hypertension is needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Unilateral lung hyperinflation and herniation as a manifestation of intrinsic PEEP.

In a 64-year-old ventilated patient with severe chronic obstructive pulmonary disease and extensive unilateral pneumonia, intrinsic PEEP became recognized when the chest roentgenogram showed unilateral lung hyperinflation and herniation of a large bulla to the contralateral hemithorax. The use of an on-line suction catheter may have contributed to the development of intrinsic PEEP. Removal of the catheter resulted in roentgenographic and clinical improvement.

Group education sessions and compliance with nasal CPAP therapy.

STUDY OBJECTIVES: To determine an effective means of improving compliance with nasal continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). DESIGN: Retrospective chart review. SETTING: An outpatient clinic at a Veterans Affairs Medical Center. PATIENTS: Seventy-three patients with OSA. INTERVENTIONS: Hour meters on CPAP machines provided documentation of nightly machine use. A 2-h group CPAP clinic, scheduled every 6 months, provided education, support, symptom treatment, and equipment monitoring for all CPAP patients. RESULTS: Twenty-five patients had hour meter readings taken at their first CPAP clinic. In these patients, nightly CPAP use increased from 5.2 +/- 0.6 to 6.3 +/- 0.6 h per night after attendance at one CPAP clinic (p < 0.05). CPAP use increased from 5.2 +/- 0.5 before CPAP clinic to 6.3 +/- 0.6 h per night after attendance at all subsequent CPAP clinics for 34 patients (p < 0.05), an improvement that was sustained over 605 +/- 34 days. Twenty-nine percent of patients increased nightly CPAP use by at least 2 h, while only 6% decreased by > or = 2 h (p < 0.025). Patients receiving supplemental oxygen had higher CPAP use prior to CPAP clinic compared to patients not receiving oxygen (p < 0.05). CONCLUSIONS: Attendance in a group clinic designed to encourage patient compliance with CPAP therapy provided a simple and effective means of improving treatment of OSA.

Effects of endothelial cell injury on pulmonary vascular reactivity.

Using the thiocarbamide model of acute lung injury in rats, we found that alpha-naphthylthiourea (ANTU) caused lung endothelial cell injury, as evidenced by increased permeability edema and decreased angiotensin I conversion. These effects were associated with enhanced pulmonary vascular reactivity. Recurrent ANTU lung injury caused pulmonary hypertension. The water-soluble thiocarbamide thiourea caused cultured vascular endothelial cells to release neutrophil chemoattractant activity. We speculate that endothelial cell injury may modulate the function of vascular smooth muscle and blood leukocytes.

Compliance with CPAP therapy in older men with obstructive sleep apnea.

OBJECTIVES: Factors specifically affecting compliance with continuous positive airway pressure (CPAP) in older patients with obstructive sleep apnea (OSA) have not been described. The purpose of this study is to determine which factors are associated with compliance and noncompliance in older patients, a growing segment of the population. DESIGN: A retrospective chart review of older male patients prescribed CPAP therapy for OSA over an 8-year period. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: All patients age 65 and older for whom CPAP therapy had been prescribed for treatment of OSA in the past 8 years. MEASUREMENTS: Records of all older male patients prescribed CPAP therapy for OSA over the last 8 years were reviewed. Compliance was defined by time-counter readings averaging 5 or more hours of machine run-time per night. RESULTS: Of 33 older male patients with OSA studied, 20 were found to be compliant and 13 noncompliant with nasal CPAP therapy. The mean age (+/- SEM) at the time of diagnosis of OSA in the compliant group was 68 (+/-1) years, whereas that of the noncompliant group was 72 (+/-1) years (P <.05). Of the compliant patients, 95% attended a CPAP patient education and support group, whereas only 54% of noncompliant patients attended (P =.006). Resolution of initial symptoms of OSA with CPAP therapy was significantly associated with compliance. Symptom resolution occurred in 90% of compliant patients and in only 18% of noncompliant patients (P <.0002). Factors that were significantly associated with noncompliance with CPAP were cigarette smoking, nocturia, and benign prostatic hypertrophy (BPH). Of noncompliant patients, 82% complained of nocturia, whereas only 33% of compliant patients complained of nocturia (P =.02). BPH was diagnosed in 62% of noncompliant patients and in only 15% of compliant patients (P =.004). Diuretic use was more common in the compliant group and, therefore, was not a cause of increased nocturia in noncompliant patients. CONCLUSION: In older male patients with OSA, compliance with CPAP therapy is associated with attendance at a patient CPAP education and support group. Resolution of symptoms with therapy also appears to be associated with enhanced compliance. In addition, we found an association between nocturia and the existence of BPH in older men with OSA who are not compliant with nasal CPAP. Larger observational studies should be performed to confirm these findings, and, if so confirmed, then further studies to determine whether treatment of BPH in older men with OSA improves compliance with CPAP.

Effect of ATP-induced permeabilization on loading of the Na+ probe SBFI into endothelial cells.

The fluoroprobe sodiumbinding benzofuran isophthalate (SBFI) is used to measure intracellular cytosolic sodium concentration ([Na]i). A problem with the use of this probe is the difficulty in loading it into cells. ATP reversibly increases membrane permeability of some cells via activation of receptors of the tetrabasic form of ATP (ATP4-). We investigated the effect of ATP-induced membrane permeabilization on loading of the acetoxymethyl ester (AM) form of SBFI (SBFI-AM) into bovine pulmonary arterial endothelial cells. Monolayers were incubated in a series of solutions that reversibly opened pores, loaded the fluoroprobe, and finally sealed the proes. ATP (1-5 mM) or 3'-O-(4-benzoyl)benzoyl-ATP (0.1-1 mM), an analogue 30-100x more specific for ATP4- receptors, was utilized to permeabilize the cell membrane. The signal-to-background ratio of the intracellular SBFI fluorescent signal was used as an indicator of the effectiveness of dye loading. ATP and 3'-O-(4-benzoyl)benzoyl-ATP significantly increased the signal-to-background ratio compared with the values obtained with the standard dye-loading procedure without ATP, indicating that permeabilization increased SBFI-AM entry into the cells. The permeabilization procedure produced a small decrease in cell viability, as determined with a fluorescent viability assay (ethidium dimer uptake), compared with the standard method of loading SBFI-AM. We used the procedure to measure baseline [Na]i and changes in [Na]i after the administration of ouabain (10(-4) M) and monensin (10(-5) M). Baseline [Na]i with this procedure (19.7 +/- 2.7 mM; n = 15 monolayers) was similar to measurements made in other cell types with the standard method of loading the probe. We conclude that 1) the ATP-induced permeabilization technique is an improved dye-loading method for SBFI-AM in endothelial cell monolayers that facilitates measurement of [Na]i and 2) these data suggest the presence of an ATP4 pore-forming mechanism in this cell type.

Cutaneous leucocytoclastic vasculitis associated with oxacillin.

A 67-year-old man who was treated with oxacillin for one week because of Staphylococcus aureus bacteremia, developed renal failure and diffuse, symmetric, palpable purpuric lesions on his feet. Necrotic blisters were noted on his fingers. Skin biopsies showed findings diagnostic of leucocytoclastic vasculitis. Oxacillin was discontinued and patient was treated with corticosteroids. The rash disappeared after three weeks and renal function returned to normal. Leucocytoclastic vasculitis presents as palpable purpura of the lower extremities often accompanied by abdominal pain, arthralgia, and renal involvement. Etiologic factors or associated disorders include infections, medications, collagen vascular disease and neoplasia. However, in half of the cases no etiologic factor is identified. Usually it is a self-limited disorder, but corticosteroid therapy may be needed in life-threatening cases since early treatment with corticosteroids in severe cases can prevent complications. Oxacillin should be included among the drugs that can cause leucocytoclastic vasculitis.

Pulmonary hypertensive response to foreign body microemboli.

Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.

Differences in nucleotide effects on intracellular pH, Na+/H+ antiport activity, and ATP-binding proteins in endothelial cells.

Bovine (BPAEC) and human (HPAEC) pulmonary artery endothelial cell monolayers were incubated with either ATP, ATP analogues, or UTP, followed by measurement of intracellular pH (pHi) and the rate of recovery from acidosis. ATP increased baseline pHi and the rate of acid recovery in BPAEC. This response was inhibited by the amiloride analogue, methyisobutylamiloride, demonstrating that activation of the Na+/H+ antiport was responsible for the increase in baseline pHi and the recovery from acidosis. This response had the features of both a P2Y and P2U purinergic receptor, based on the responses to a series of ATP analogues and UTP. In contrast, none of the nucleotides had any significant effect on pHi and Na+/H+ antiport activity in HPAEC. This difference in the response to extracellular nucleotides was not due to a difference in ATP metabolism between cell types, since the ectonucleotidase-resistant analogue. ATP gamma S, also had no effect on HPAEC. Analogues of cAMP had no effect on pHi or acid recovery in either cell type. Incubation of BPAEC and HPAEC with the photoaffinity ligand [32P] 8-AzATP indicated that both BPAEC and HPAEC possess an ATP-binding protein of 48 kDa. However, BPAEC exhibited an additional binding protein of 87 kDa. Thus, the contrasting response to extracellular ATP between bovine and human pulmonary artery endothelial cells may be related to differences in the signal transduction pathway leading to antiport activation, including different ATP-binding sites on the cell membrane.

Pulmonary hypertension update.

Research into the causes and treatment of primary pulmonary hypertension (PPH) has provided new hope for this disease. This article reviews recent developments in its pathogenesis, classification, and treatment. An approach to diagnosing the patient with pulmonary hypertension also is outlined.