Biomedical subjects

L Kobzik

Publications and source records attributed to L Kobzik.

At least 163 records · Page 9Linked to original sources

PubMed1989

Oxygen free radicals mediate ischemia-induced lung injury.

Lower torso ischemia leads during reperfusion to leukocyte (white blood cell)-dependent lung injury. This study tests the intermediary role of oxygen free radicals (OFRs) in mediating this event. Chronically instrumented anesthetized sheep underwent 2 hours of bilateral hindlimb ischemia. In untreated control animals (n = 7), 1 minute after tourniquet release, mean pulmonary artery pressure rose from 13 to 38 mm Hg (p less than 0.05), whereas pulmonary artery wedge pressure was unchanged from 4 mm Hg. The pulmonary hypertension was temporally related to an increase in plasma thromboxane (Tx) B2 levels from 211 to 735 pg/ml (p less than 0.05). At 30 minutes of reperfusion lung-lymph TxB2 levels rose from 400 to 1005 pg/ml (p less than 0.05). This coincided with an increase in lung-lymph flow from 4.3 to 8.3 ml/30 min (p less than 0.05), which remained elevated for 2 hours, an unchanged lymph/plasma protein ratio, and a rise in lymph protein clearance from 2.6 to 4.6 ml/30 min (p less than 0.05). These changes are consistent with increased lung microvascular permeability. White blood cell count fell during the first hour of reperfusion from 6853 to 3793/mm3 (p less than 0.05), and lung histologic findings showed marked leukosequestration relative to sham animals (n = 3). Pretreatment with the OFR scavengers, superoxide dismutase and catalase both conjugated to polyethylene glycol (n = 6) blunted the rise in mean pulmonary artery pressure to 19 mm Hg (P less than 0.05) and prevented the increase in plasma and lymph TxB2 lymph flow, and lymph protein clearance (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗

PubMed1988

Recombinant granulocyte-macrophage colony-stimulating factor down-regulates expression of IL-2 receptor on human mononuclear phagocytes by induction of prostaglandin E.

Recent studies have shown that normal human alveolar macrophages and blood monocytes, as well as HL-60 and U937 monocyte cell lines, newly express IL-2R after stimulation with rIFN-gamma or LPS. In addition, macrophages transiently express IL-2R in vivo during immunologically mediated diseases such as pulmonary sarcoidosis and allograft rejection. We therefore investigated in vitro factors that modulate macrophage expression of IL-2R. IL-2R were induced on normal alveolar macrophages, blood monocytes, and HL-60 cells using rIFN-gamma (24 to 48 h at 240 U/ml), and cells were cultured for an additional 12 to 24 h with rIL-2 (100 U/ml), recombinant granulocyte-macrophage CSF (rGM-CSF, 1000 U/ml), rGM-CSF plus indomethacin (2 X 10(-6) M), PGE2 (0.1 to 10 ng/ml), 1 X 10(-6) M levels of caffeine, theophylline, and dibutyryl cyclic AMP, or medium alone. IL-2R expression was quantitated by cell ELISA (HL-60 cells) or determined by immunoperoxidase staining (alveolar macrophages, blood monocytes, and HL-60 cells), using anti-Tac and other CD25 mAb. PGE production was assayed by RIA. We found greater than 95% of alveolar macrophages, monocytes, and HL-60 cells expressed IL-2R after rIFN-gamma treatment and remained IL-2R+ in the presence of IL-2R or medium alone. By comparison, greater than 95% of cells induced to express IL-2R became IL-2R- after addition of rGM-CSF, and the culture supernatants from GM-CSF-treated cells contained increased levels of PGE. This inhibition of macrophage IL-2R expression by rGM-CSF was blocked by indomethacin, and IL-2R+ macrophages became IL-2R- after addition of PGE2 alone. These findings indicate GM-CSF down-regulates IL-2R expression by human macrophages via induction of PGE synthesis. Moreover, a similar down-regulation of IL-2R expression was seen after stimulation with caffeine, theophylline, or dibutyryl cyclic AMP. Hence, GM-CSF, PGE, and other pharmacologic agents that act to increase intracellular levels of cAMP may play a modulatory role, antagonistic to that of IFN-gamma on cellular expression of IL-2R by human inflammatory macrophages in vivo.

Cell Line↗

PubMed1988

Lower torso ischemia-induced lung injury is leukocyte dependent.

Lower torso ischemia leads on reperfusion to sequestration of polymorphonuclear leukocytes (PMN) in the lungs and increased permeability. This study tests the role of circulating leukocytes (WBC) in mediating this lung injury. Anesthetized sheep prepared with chronic lung lymph fistulae underwent 2 hours of bilateral hind limb tourniquet ischemia. In untreated controls (n = 7), 1 minute after reperfusion there were transient increases in mean pulmonary arterial pressure (MPAP) from 13 to 38 mmHg (p less than 0.05) and pulmonary microvascular pressure (Pmv) from 7 to 18 mmHg (p less than 0.05), changes temporally related to a rise in plasma thromboxane (Tx) B2 levels from 211 to 735 pg/ml (p less than 0.05). Lung lymph TxB2 levels rose from 400 to 1005 pg/ml at 30 minutes (p less than 0.05), and remained elevated longer than plasma levels. Lung lymph flow (QL) rose from 4.3 to 8.3 ml/30 minutes (p less than 0.05) after 30 minutes of reperfusion and remained elevated for 2 hours. The lymph/plasma (L/P) protein ratio was unchanged from 0.6, while the lymph protein clearance increased from 2.6 to 4.6 ml/30 minutes (p less than 0.05), suggesting increased microvascular permeability. WBC counts decreased within the first hour of reperfusion from 6853 to 3796/mm3 (p less than 0.05), and lung histology after 2 hours showed proteinaceous exudates and leukosequestration of 62 PMN/10 high-powered fields (HPF), higher than the 22 PMN/10 HPF (p less than 0.05) in sham animals (n = 3). Recruitment of the pulmonary vasculature by left atrial balloon inflation (n = 3) resulted in a rise in MPAP to 20 mmHg. After 3 hours of balloon inflation, QL stabilized at 9.8 ml/15 minutes, and a pressure-independent L/P protein ratio of 0.3 was achieved. During reperfusion, QL increased further to 11.2 ml/15 minutes, the L/P ratio rose to 0.56 and the calculated osmotic reflection coefficient decreased from 0.70 to 0.44, documenting an increase in lung microvascular permeability. In contrast to these untreated ischemic controls, sheep (n = 7) rendered leukopenic with hydroxyurea or nitrogen mustard and having a total WBC count of 760/mm3 and PMN count of 150/mm3 did not manifest reperfusion-induced increases in MPAP, Pmv, QL, lymph protein clearance, or lung lymph. TxB2 level (p less than 0.05). Plasma TxB2 levels rose slightly at 30 minutes from 199 to 288 pg/ml (p less than 0.05). Lung histology was normal. These data indicate that WBC mediate the ischemia-induced increase in pulmonary microvascular permeability.

Animals↗

PubMed1988

Inhibition of thromboxane (Tx) synthesis by free radical scavengers.

Treatment with thromboxane (Tx) synthase inhibitors or free radical scavengers has been shown to afford protection from renal ischemia. Since free radicals are closely associated with thromboxane (Tx) synthesis, this study examines the thesis that free radical scavengers inhibit formation of Tx. Anesthetized rats (n = 42) underwent right nephrectomy. By random choice, before 45 min of left renal pedicle clamping, rats received: 0.5 ml dextrose placebo IV (n = 6); the hydroxyl radical scavenger dimethyl-thiourea (DMTU), 500 mg/kg IV (n = 10); or the superoxide scavenger superoxide dismutase (SOD), 24,000 Sigma Units (SU)/kg IV (n = 12). This dose of SOD was repeated before release of the clamp. Treatment with DMTU and SOD decreased plasma TxB2 levels following 5 min of reperfusion from 2,480 pg/ml in dextrose treated controls to 1,155 pg/ml (p less than 0.01) and 1,419 pg/ml (p less than 0.03), respectively. At 24 hr, DMTU and SOD therapy decreased creatinine from 3.0 mg/dl in controls to 1.6 mg/dl (p less than 0.01) and 2.1 mg/dl (p less than 0.05), respectively. At 24 hr, DMTU but not SOD decreased left renal weight from 113 to 94% (p less than 0.0003) of the weight of the previously removed right kidney, and histologically prevented acute tubular necrosis (p less than 0.05). In nephrectomized but nonischemic sham control rats (n = 7) plasma TxB2 and 6-keto-PGF1 alpha concentrations were 757 pg/ml and 82 pg/ml, creatinine level 0.9 mg/dl and kidney weight 94% of the previously removed right kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Selective lung leukosequestration after complement activation.

This study tests whether activated complement leads to a selective entrapment of polymorphonuclear leukocytes (PMN's) in the lungs. Awake sheep were infused for 5 min with zymosan-activated plasma (ZAP, 2.5 mg/ml) at a rate of 5 ml/min into the superior vena cava (IV, n = 4) or intra-arterially into the aortic arch or femoral artery (IA, n = 8). At the end of IV infusion, leukocyte counts fell from 8,862 to 1,631/mm3 (P less than 0.01). PMN counts across the lungs decreased by 74%. There were increases in plasma thromboxane (Tx) B2 from 114 to 2,733 pg/ml (P less than 0.01), mean pulmonary arterial pressure from 12 to 42 mmHg (P less than 0.01), and physiological shunt from 13 to 25% (P less than 0.05). Within 1 h lymph TxB2 levels had risen from 301 to 4,916 pg/ml (P less than 0.01), lung lymph flow (QL) rose from 3.7 to 11.1 ml/30 min (P less than 0.05), lymph-to-plasma protein ratio (L/P) remained unchanged at 0.63, and lymph protein clearance increased from 2.3 to 7.5 ml/30 min (P less than 0.05). Leukosequestration, quantitated by capillary PMN counting and by assaying the granulocyte marker myeloperoxidase, occurred relative to sham animals (P less than 0.05) in the lung and spleen but not in other organs. Intra-arterial ZAP infusion led to changes that were similar in magnitude and timing to the IV group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Role of plasminogen activator in degradation of extracellular matrix protein by live human alveolar macrophages.

Recent evidence indicates that human alveolar macrophages can degrade purified elastin in vitro by a cell contact-dependent process involving acidic proteinases of the cysteine proteinase class. It is unclear to what extent these cells can degrade elastin within a natural extracellular matrix. To address this question, we cultured live human alveolar macrophages on elastin-rich, 3H-lysine-labeled, extracellular matrices deposited by rat smooth muscle cells in vitro. Under various culture conditions, we then measured release of total radioactivity from the matrices during co-culture with cells as well as net loss of desmosine/isodesmosine as a specific marker of elastin degradation. Live macrophages adhered to and progressively solubilized matrix protein at a slow rate (approximately 5 micrograms/10(6) cells/24 h) but the rate of solubilization increased more than 15-fold in the presence of plasminogen. The elastin component of the complicated matrix was not measurably degraded in the absence of plasminogen, but in medium containing plasminogen, 3.5 X 10(6) macrophages degraded 25 +/- 8 micrograms of elastin in 72 h. After pretreatment of matrices with trypsin to remove glycoprotein elements, live cells degraded 16 +/- 4 micrograms of elastin under plasminogen-free conditions. The addition of serum to the medium (1 to 5%) inhibited degradation of elastin within whole matrices (approximately 50% compared to serum-free medium containing plasminogen) but had no effect on degradation of elastin in trypsin-pretreated matrices. An active site inhibitor of cysteine proteinases, Z-phenylalanine-phenylalanine-diazomethylketone, blocked approximately 50% of the elastin degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1988

Isolation and antigenic identification of hamster lung interstitial macrophages.

Lung interstitial macrophages (IMs) are a large, distinctive population of cells with important proliferative capacities. Characterization of their role in health and disease has been hampered by inadequate methods to separate interstitial from residual alveolar macrophages (AMs) in preparations of individual mononuclear cells from lung tissue. In this study, a specific cell-surface antigen (HAM1) present on more than 90% of hamster AMs, but not expressed by hamster IMs, was used to distinguish these populations. After collagenase digestion of lung tissue slices from exhaustively lavaged and perfused hamster lungs, mononuclear phagocytes were isolated by density gradient centrifugation. The mean yield of lung digest macrophages (3.9 +/- 1.9 (SD) x 10(6] was comparable to the yield of lavaged AMs (4.2 +/- 1.9 x 10(6]. The proliferative capacity of lavaged AMs, blood monocytes, and lung digest macrophages was compared using a soft-agar colony-forming unit (CFU) assay. Both lung digest macrophages and blood monocytes had significantly more CFUs (68.7 +/- 2.6 and 53.5 +/- 8.4 CFU/10(3) cells [mean +/- SEM], respectively) than did AMs (16.5 +/- 1.7) (p less than 0.01). To further define the composition of the lung digest macrophage population, flow cytometric analysis of fixed cells from six experiments was performed using a mouse monoclonal antibody specific for the HAM1 antigen found only on AMs. The lung digest macrophage population consisted of both antigen-negative IMs (78.2% +/- 3.7% [SEM]; n = 6) and antigen-positive, residual AMs (21.8% +/- 3.7%). Morphometric counts confirmed that substantial numbers of AMs are left behind after lavage and contribute to macrophages obtained from lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Vasodilator prostaglandins (PG) prevent renal damage after ischemia.

Thromboxane (Tx) synthase but not cyclo-oxygenase inhibitors prevent acute tubular necrosis (ATN) after renal ischemia, a phenomenon believed to be due to stimulation of the endogenous production of vasodilating prostaglandins (PG). This study directly tests that vasodilating PG protect against the consequences of renal ischemia. Anesthetized, 500-g rats had right nephrectomy and 45 minutes of left renal pedicle clamping or sham clamping. The rats were treated with intravenous (I.V.) saline 1.9 mL/h starting 40 minutes after clamping or sham clamping. All rats except the sham group (N = 8) were pretreated 1 hour before ischemia with ibuprofen (12 mg/kg) to prevent prostanoid synthesis. Beginning 5 minutes before clamp release, the rats were treated intravenously for 2 hours with: saline vehicle (N = 9), PGE1 400 ng/kg/min (N = 6), nitroprusside 4 micrograms/kg/min (N = 8), or dopamine 3 micrograms/kg/min (N = 11). After 24 hours, sham rat creatinine level was 0.5 mg/dL and weight of the left kidney was 86.5% of the previously removed right kidney. Compared with sham rats, ischemia and saline treatment resulted in a rise in creatinine level to 2.7 mg/dL (p less than 0.05) and a rise in kidney weight to 101.9% (p less than 0.05); PGE1 led to a creatinine level of 1.1 mg/dL, a value lower than that of the rats treated with saline (p less than 0.05), and a kidney weight of 92.0%, a value similar to that of sham rats; nitroprusside and dopamine led to a rise in creatinine levels to 3.2 mg/dL (p less than 0.05) and 2.3 mg/dL (p less than 0.05), respectively, as well as a rise in kidney weight to 108.0% (p less than 0.05) and 105.4% (p less than 0.05), respectively. Histologic examination showed ATN in rats treated with saline, nitroprusside, and dopamine, but not in rats treated with PGE1. These results indicate that PGE1 protects the cyclo-oxygenase-treated kidney against ischemia-induced ATN.

Acute Kidney Injury↗

PubMed1987

Pulmonary leukosequestration induced by hind limb ischemia.

Lower torso ischemia leads to acute respiratory failure, an event associated with the accumulation of inflammatory cells in the lungs. This study tests whether ischemia-induced eicosanoid synthesis leads to polymorphonuclear leukocyte (PMN) accumulation in the lungs. Anesthetized rats (N = 51) were randomized into five groups: nonischemic sham rats (N = 10); the remaining four groups were rats made ischemic for 4 hours with bilateral thigh tourniquets treated just before tourniquet release with saline vehicle (N = 17): the thromboxane (Tx) synthase inhibitor OKY-046 (Ono Pharmaceutica, Osaka, Japan) 2 mg/kg intravenously every 2 hours (N = 8); the lipoxygenase inhibitor diethylcarbamazine (DEC) (Sigma, St. Louis, MO) 0.2 mg/kg/min intravenously (N = 8); the platelet-activating factor receptor antagonist SRI (Sandoz Inc., East Hanover, NJ) 63-072 3 mg/kg intravenously every 30 minutes (N = 8). Four hours after ischemia, plasma TxB2 levels in the ischemic placebo-treated group was 3570 +/- 695 pg/mL, compared with 495 +/- 73 pg/mL in sham rats (p less than 0.001). Lung microscopy showed foci of proteinaceous exudate in alveoli and 121 +/- 10 PMN/20 high power fields (HPF) compared with 59 +/- 9 PMN/20 HPF in the sham group (p less than 0.001). One day after ischemia PMN accumulations remained elevated at 119 PMN/20 HPF. Pretreatment with OKY-046 led to reduced TxB2 levels of 149 +/- 17 pg/mL, normal lung histology, and 83 +/- 13 PMN/20 HPF, a value similar to that of the sham group and lower than that of the placebo-treated group (p less than 0.05). Treatment with DEC yielded TxB2 levels of 1419 +/- 492 pg/mL, which was lower than that of the placebo group (p less than 0.05) but higher than that of the sham group (p less than 0.05). Microscopy showed normal lungs with 79 +/- 7 PMN/20 HPF lower than the placebo group (p less than 0.05). SRI 63-072 did not inhibit Tx synthesis or leukosequestration in the lungs. Platelet counts decreased in all groups relative to sham animals (p less than 0.05). The results indicate that Tx synthesis induced by ischemia moderates PMN accumulations in the lungs. Inhibition of lipoxygenase is believed to prevent PMN accumulations both by limiting leukotriene-induced Tx synthesis as well as by limiting production of chemoattractants.

Animals↗

PubMed1987

Pulmonary hypertension and leukosequestration after lower torso ischemia.

Ischemia stimulates thromboxane (Tx) synthesis. This study tests the hypothesis that the cardiopulmonary dysfunction that may follow aortic declamping is related to Tx. Anesthetized dogs (N = 15) were subjected to 4 hours of infrarenal aortic cross-clamping. In untreated control animals (N = 7), plasma levels of TxB2 rose from 654 +/- 74 pg/mL to 1238 +/- 585 pg/mL at 5 min (p less than 0.05), and to 3174 +/- 912 pg/mL 3 hours after declamping (p less than 0.05). Mean pulmonary artery pressure (MPAP) rose 5 min after declamping from 13 +/- 2 mmHg to 21 +/- 2 mmHg (p less than 0.05). Cardiac Index (CI) declined during ischemia from 181 +/- 30 mL/kg.min to 128 +/- 16 mL/min.kg (p less than 0.05), and to 80 +/- 8 mL/min.kg after 4 hours of reperfusion (p less than 0.05). Platelet counts declined but platelets labeled with In 111 did not accumulate in the lungs, whereas quantitative counts of polymorphonuclear leukocytes (PMN) in the lungs 4 hours after declamping yielded 213 +/- 33 PMN/25 high power fields (HPF) in dependent areas of the lung and 153 +/- 26 PMN/25 HPF in nondependent areas. The wet/dry weight ratio of the lungs was not elevated, although foci of proteinaceous exudate and PMNs in alveoli were noted. Another group of dogs (N = 8) were pretreated by random choice with the Tx synthase inhibitor OKY-046 2 mg/kg IV every 2 hours, which led to: lower TxB2 levels at baseline 95 +/- 35 pg/mL (p less than 0.05), 5 min after ischemia 140 +/- 93 pg/mL and after 3 hours of reperfusion 122 +/- 36 (p less than 0.05); lower MPAP, 16 +/- 2 mmHg (p less than 0.05); higher CI throughout (p less than 0.05); normal histology and reduced pulmonary PMN sequestration both in dependent 127 +/- 15 PMN/25 HPF and nondependent areas of the lungs 95 +/- 11 PMN/25 HPF (p less than 0.05). In animals undergoing sham ischemia (N = 3), levels of TxB2 and cardiopulmonary function remained unchanged from baseline. There were 150 PMN/25 HPF in dependent and 85 PMN/25 HPF in nondependent lung areas. The results indicate that ischemia-generated Tx mediates a rise in MPAP, a fall in CI, and PMN entrapment in the lungs.

Animals↗

PubMed1987

Nuclear magnetic resonance spectroscopy of acute and evolving pulmonary hemorrhage. An in vitro study.

The proton NMR relaxation times of lung tissue were determined in a rabbit model of acute and evolving pulmonary hemorrhage (PH). Pure PH was simulated by injecting blood into a single lobe using endobronchial catheterization. In vitro spectroscopic measurements of T1 and T2 were made and total water content was determined on lung samples that were excised at regular intervals. T1 and T2 were markedly longer in lungs with acute PH than in normal lungs (T1: 818 +/- 44 vs. 643 +/- 4 msec; T2 164.0 +/- 16.3 vs. 88.1 +/- 3.4 msec). Within the first 24 hours, evolving PH was characterized by a rapid and progressive decrease in T1 (-50%) and T2 (-57%). Up to seven days after the instillation of blood, the T1 (450 +/- 43 msec) and T2 (69.7 +/- 1.9 msec) of lung with modeled PH remained below values of normal lung. The observed shortening of the relaxation times of lung disease with PH was closely paralleled by a decrease in tissue water content.

Animals↗

PubMed1987

A high plasma prostaglandin to thromboxane ratio protects against renal ischemia.

Pretreatment with the thromboxane synthase inhibitor OKY-046 but not the cyclo-oxygenase inhibitor ibuprofen protects against ischemia-induced acute tubular necrosis. However, ibuprofen together with the vasodilating agent prostaglandin E1 is protective. This suggests that a high prostaglandin to thromboxane ratio is the major factor operative in preventing tubular necrosis, the subject of this study. Rats that had unilateral nephrectomy (n = 60) with the exception of rats that had sham operations (n = 8) underwent 45 minutes of left renal pedicle clamping. Thirty minutes before the operation, the rats received either a saline solution or a thromboxane synthase inhibitor that was given intravenously. The inhibitors OKY-046 (2 milligrams per kilogram, n = 10), UK38485 (1 milligram per kilogram, n = 9) and U63357A (10 milligrams per kilogram, n = 10) were given as a single bolus while the inhibitor CGS13080 (0.1 milligram per kilogram, n = 9, and 1.0 milligram per kilogram, n = 7) was given by constant infusion and continued for 60 minutes after reperfusion. With saline solution therapy, five minutes after reperfusion, thromboxane B2 increased from 154 to 2,537 picograms per milliliter (p less than 0.00001) and 6-keto-prostaglandin F1 alpha increased from 51 to 266 picograms per milliliter (p less than 0.004). At 24 hours, the creatinine level increased from 0.5 to 2.8 milligrams per deciliter (p less than 0.00001). Only OKY-046 yielded a creatinine level at 24 hours of 1.2 milligrams per deciliter, a value lower than that for those in the saline solution control group (p less than 0.002). Furthermore, OKY-046 led to the highest prostaglandin to thromboxane ratio (p less than 0.035). The five other ratios which occurred after drug therapy were inversely related to the decrease in the creatinine value (r = -0.93, p less than 0.02). Histologically, OKY-046 was the only thromboxane synthase inhibitor to prevent acute tubular necrosis (p less than 0.05). Results show that a high prostaglandin to thromboxane ratio protects against acute tubular necrosis.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Detection of lymphokines and lymphokine receptors in pulmonary sarcoidosis. Immunohistologic evidence that inflammatory macrophages express IL-2 receptors.

In an investigation of the immunopathogenesis of sarcoidosis, the authors undertook the tissue localization of those lymphokines and lymphokine receptors which are known to play a central role in T-cell and macrophage activation. Using monoclonal antibodies and an ABC immunoperoxidase technique. They determined the distribution of gamma interferon (IFN-g), interleukin-2 (IL-2), and corresponding IL-2 receptors (IL-2R), plus T cells and T cell subsets, B cells, and macrophages within thoracic lymph nodes and lung specimens of 9 patients with active pulmonary sarcoidosis. Epithelioid and multinucleate giant cells within sarcoid granulomas of all specimens showed membrane labeling for IL-2R and IFN-g, in addition to IL-2, suggesting that these cells indeed express functional IL-2 receptors. Infiltrating T cells, largely T4+, were also IL-2R+, and many showed IL-2 and IFN-g labeling. By comparison, macrophages within sections of normal lung or lymph node failed to stain for IL-2, IL-2R, or IFN-g. These immunohistologic studies extend recent in vitro observations by these authors and others that normal human blood monocytes and alveolar macrophages are induced by IFN-g or IL-2 to express functional membrane-bound IL-2 receptors. The in vivo expression of IL-2R by mononuclear phagocytes in pulmonary sarcoidosis is demonstrated, and a new role is suggested for T-cell-derived lymphokines in macrophage activation.

Antibodies, Monoclonal↗

PubMed1986

Pulmonary and systemic consequences of localized acid aspiration.

Acid aspiration may recruit a generalized inflammatory reaction that can potentiate the local injury. After surgical isolation of bronchi in a group of 15 dogs, 1 milliliter per kilogram of 0.37 normal hydrochloric acid was instilled into either side. After five minutes, platelet and white blood cell counts fell to 10,000 and 1,000 per cubic millimeter (p less than 0.05). Platelet aggregates were noted in blood smears. 111Indium-platelet activity doubled over both the aspirated and nonaspirated lung (p less than 0.05). Physiologic dead space rose from 18 to 67 per cent and to 46 per cent in the aspirated and nonaspirated lung (p less than 0.05). Physiologic shunt increased from 12 to 47 per cent and to 43 per cent (p less than 0.05) on the two sides. Plasma thromboxane B2 levels at 30 minutes rose from 0.28 to 0.93 nanograms per milliliter (p less than 0.05). Edema fluid from the aspirated lung had thromboxane B2 values of 2.87 nanograms per milliliter, indicating pulmonary synthesis. Within five minutes of aspiration, systemic effects were prominent; mean arterial pressure fell from 114 to 46 milliliters of mercury (p less than 0.05), and the cardiac index fell 24 per cent from 106 to 81 milliliters per kilogram per minute (p less than 0.05) along with an 18 per cent decrease in contractility of a rat papillary muscle bathed in plasma from the aspirated dog. Mean pulmonary arterial pressure rose from 12 to 18 millimeters of mercury (p less than 0.05). Despite fluid infusion at 36 milliliters per kilogram per hour to keep wedge pressure constant at 5.5 millimeters of mercury, and sampling of one-third the blood volume, hemoglobin concentration rose 0.9 grams per cent (p less than 0.05) indicating increased microvascular permeability. At autopsy, the aspirated and nonaspirated lung were indistinguishable with congestion, interstitial hemorrhage, and white blood cell infiltrates. Systemic organs showed vascular congestion and edema. These data demonstrate that local aspiration leads to generalized inflammatory sequelae with cardiopulmonary failure.

Animals↗

PubMed1985

Immunohistologic analysis of a human pulmonary alveolar macrophage antigen.

PAM1 is a 200-kDa polypeptide antigen present on lavaged human alveolar macrophages but not on monocytes, peritoneal macrophages, breast milk macrophages, or other normal hematopoietic cells studied by flow cytometry. We have characterized the distribution of expression of this antigen by cells in tissues by using immunohistologic techniques. Normal and diseased lung as well as lymph nodes, spleen, kidney, liver, GI tract, and skin were studied. PAM1 was expressed strongly on the surface and weakly in the cytoplasm of most alveolar macrophages in all 15 of the lung specimens. Occasional interstitial macrophages had weak to moderate staining for this antigen but the majority did not stain. The distribution, pattern, and intensity of staining for PAM1 was the same in normal lung specimens and those with interstitial pneumonitis, despite the increase in mononuclear cells in the latter. Dermal histiocytes and Kuppfer cells expressed PAM1 weakly. Sinus histiocytes in lymph nodes were moderately to strongly positive. Although lymphoid cell suspensions (tonsil) were negative by flow cytometry, five of six lymph nodes had positive cells by immunohistology. PAM1 was also detected on endothelial cells of splenic sinusoids in all 6 specimens but not on any other endothelium. Hence, while PAM1 is expressed most strongly on alveolar macrophages, it can also be demonstrated in other locations using sensitive immunohistologic techniques. Since circulating monocytes are antigen negative and some lung interstitial macrophages bear antigen, PAM1 may be a useful marker for studies of the differentiation of mononuclear cells in the lung.

Antibodies, Monoclonal↗

PubMed1985

The detection of inflammation in collapsed lung by alterations in proton nuclear magnetic relaxation times.

The purpose of this study was to establish the proton NMR relaxation times of collapsed but otherwise normal lung tissue and to determine whether an inflammatory process within a collapsed lung can be detected by alterations in relaxation times. The lungs of three groups of rabbits were studied: group A (n = 7) had a sterile collapse of one lung for two days. The two other groups also had one lung collapsed, but with bacterial (group B, n = 6) or chemically induced (group C; n = 6) pneumonitis superimposed. The contralateral lung, which was acutely deflated at the time of thoracotomy, served as a control in each animal. T1, T2 and the total water content were measured on freshly excised lung samples. In group A, there was no significant difference in T1 (606 +/- 14* ms vs. 595 +/- 18 ms;* = SEM) or T2 (80.6 +/- 1.7 ms vs. 78.4 +/- 2.6 ms) between the collapsed and the control lung tissue. In each animal in groups B and C, T2 was longer in the collapsed lung with superimposed pneumonitis than in the control lung tissue (group B: 116.8 +/- 6.9 ms vs. 82.9 +/- 1.8 ms, P less than .001; group C: 120.5 +/- 5.9 ms vs. 86.0 +/- 1.5 ms, P less than .001). T1 changes were similar, but less marked. There was a linear relationship between the relaxation times and the total water content of the lung samples (T1:r = 0.87; T2:r = 0.91). It is concluded that proton NMR may have a potential in detecting disease such as inflammation in collapsed lung tissue based on differences in relaxation parameters compared with normal lung areas.

Animals↗

PubMed1985

Prostacyclin and thromboxane A2 moderate postischemic renal failure.

Since prostacyclin (PGI2) is known to regulate renal cortical blood flow and since ischemia stimulates thromboxane (Tx) A2 synthesis, the role of these prostanoids in moderating the response to renal ischemia was studied in the rat. At baseline, plasma TxB2 concentration in untreated animals (n = 13) was 357 pg/ml. The left renal pedicle was clamped for 45 minutes after a right nephrectomy (n = 16), which led after 5 minutes of reperfusion to a rise in TxB2 to 2825 pg/ml (p less than 0.001), but there was no change in 6-keto-PGF1 alpha. After 24 hours creatinine levels rose from 0.4 to 3.0 mg/dl (p less than 0.001), and left renal weight rose from 94% to 117% (p less than 0.001) relative to the weight of the right kidney. In nephrectomized but nonischemic sham control rats (n = 7), creatinine level was 0.9 mg/dl and kidney weight 91% after 24 hours. Pretreatment with OKY 046 (n = 13) (2 mg/kg administered intravenously) blocked ischemia-induced TxB2 synthesis, while 6-keto-PGF1 alpha levels rose from 96 to 302 pg/ml (p less than 0.001). There was no increase in creatinine levels or kidney weight relative to the sham group. Pretreatment with ibuprofen (n = 10) (12 mg/kg) or OKY 046 and ibuprofen (n = 9) inhibited TxB2 and 6-keto-PGF1 alpha synthesis, but creatinine levels and renal weight rose (p less than 0.001). Renal histology in OKY 046-pretreated animals was equal to that in nephrectomized controls, while all other ischemic groups showed tubular necrosis. Results indicate that a high PGI2/TxA2 ratio protects against renal ischemia.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Ultrastructural analysis of a specific hamster alveolar macrophage antigen.

Alveolar macrophages of hamsters have a cell surface antigen not found on other pulmonary cells or macrophages from other sites. A specific mouse monoclonal antibody and protein A-colloidal gold were used to study the distribution of this antigen at the ultrastructural level. By quantitating the number of antigenic sites per unit linear distance of membrane of the total cell surface, it was established that this antigen is randomly distributed on the plasma membrane. Cell-to-cell heterogeneity in antigen density was correlated with other ultrastructural features of lung macrophages studied morphometrically. A strong correlation (r = 0.77) between antigen density and secondary lysosome content was found, supporting the thesis that expression of this antigen increases with macrophage age. No apparent topographic relationship of surface antigen to any cytoplasmic organelles could be inferred from the ultrastructural morphology. This study also used immuno-ultrastructural techniques to visualize stages of the internalization of labeled antigen in live cells. While some cells retained a random distribution of antigen at 0 degrees C, most showed movement of antigenic sites away from pseudopodia to clusters on more linear (less ruffled) portions of cell surface. At 37 degrees C, the antigen was internalized and could be visualized within coated pits and endocytic vacuoles. Definition of the anatomic distribution of this antigen under various conditions provides a baseline for further ultrastructural investigations of the function of this antigen.

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