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Biomedical subjects

A A Fowler

Publications and source records attributed to A A Fowler.

At least 73 records · Page 4Linked to original sources
PubMed1988

Responsiveness of guinea pig alveolar cells.

Guinea pig alveolar cells were obtained in situ via bronchoalveolar lavage. The cells were 86% macrophages (GPAM), (greater than 97% viability) with the remainder of the population comprised of lymphocytes and eosinophils. The following battery of functional assays were studied in GPAM: chemotaxis was stimulated by N-formyl-methionyl-leucine-phenylalanine (FMLP) and by phorbol-12-myristate-13-acetate (PMA) in a concentration-related manner; cytotoxicity as measured by 51Cr release from target cells +/- PMA was induced in P815 mastocytoma cells and less strongly in 3T3 normal mouse fibroblasts; release of N-acetyl-beta-D-glucosaminidase (NAGA) was stimulated by the calcium ionophore A23187, but not by PMA or the combination of PMA + A23187; superoxide anion production as measured by the reduction of ferricytochrome C was stimulated 25-fold by PMA; phagocytosis of opsonized 51Cr sheep red blood cells occurred in a time-related manner and reached its maximum after 120 min; and cell spreading, which exhibited a high rate of spontaneous spreading (76%), was only minimally stimulatable by PMA. The responsiveness of the GPAM, the ease of retrieval, and the large numbers of cells available make the guinea pig an ideal system for future study.

Animals↗
PubMed1988

Cardiopulmonary toxicity of adoptive immunotherapy.

Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.

Animals↗
PubMed1988

Cardiopulmonary effects of recombinant interleukin-2 infusion in sheep.

The systemic administration of recombinant interleukin-2 (rIL-2) with or without lymphokine-activated killer (LAK) cells, a new treatment for patients with advanced cancer, is associated with a presumed "third-space" syndrome. To further define the extent and time course of this toxicity, we established a chronic sheep model and monitored changes in systemic and central vascular pressures, cardiac function, and gas exchange during a 72-h continuous intravenous infusion of rIL-2 at a total dose of 5 (group 3) or 9 x 10(5) U/kg (group 4). At 72 h, caudal mediastinal lymph flow, histology, and extravascular lung water-to-dry lung weight ratio (EVLW/DLW) were obtained. During the rIL-2 infusion there was a dose-dependent significant decrease in systemic blood pressure and arterial Po2 and an increase in core temperature. In group 4, pulmonary arterial pressure increased from a base line of 13 +/- 5 to 21 +/- 6 mmHg (P less than 0.05). Lung lymph flow was significantly increased in groups 3 and 4 compared with animals receiving 0.9% NaCl or excipient infusions (groups 1 and 2). EVLW/DLW values were elevated in groups 3 and 4 (P less than 0.01). In animals receiving rIL-2, histological evaluation revealed a dose-dependent infiltration of lung tissue by lymphoblastoid cells that stained esterase negative. We conclude that rIL-2 infusion in doses comparable to those given to humans results in alterations in systemic and central hemodynamics, gas exchange, high-protein lung lymph flow, and infiltration of lymphoblastoid cells into the lung parenchyma.

Animals↗
PubMed1988

Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep.

We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep. Endotoxin infusion (1.3 micrograms/kg over 0.5 h) caused a rapid, transient rise in pulmonary arterial pressure (Ppa) from 16 +/- 3 to 36 +/- 10 mmHg (P less than 0.001) and pulmonary vascular resistance (PVR) from 187 +/- 84 to 682 +/- 340 dyn.s.cm-5 (P less than 0.05) at 0.5 h, followed by a persistent elevation in Ppa to 22 +/- 3 mmHg and in PVR to 522 +/- 285 dyn.s.cm-5 at 5 h in anesthetized sheep. Arterial PO2 (PaO2) decreased from 341 +/- 79 to 198 +/- 97 (P less than 0.01) and 202 +/- 161 Torr at 0.5 and 5 h, respectively (inspired O2 fraction = 1.0). SRI 63-441, 20 mg.kg-1.h-1 infused for 5 h, blocked the early rise in Ppa and PVR and fall in PaO2, but had no effect on the late phase pulmonary hypertension or hypoxemia. Endotoxin caused a gradual decrease in mean aortic pressure, which was unaffected by SRI 63-441. Infusion of SRI 63-441 alone caused no hemodynamic alterations. In follow-up studies, endotoxin caused an increase in lung lymph flow (QL) from 3.8 +/- 1.1 to 14.1 +/- 8.0 (P less than 0.05) and 12.7 +/- 8.6 ml/h at 1 and 4 h, respectively. SRI 63-441 abolished the early and attenuated the late increase in QL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Activation of pulmonary mast cells by bronchoalveolar allergen challenge. In vivo release of histamine and tryptase in atopic subjects with and without asthma.

Human mast cells likely play a significant role in human asthma. In the present study, concentrations of tryptase and histamine in bronchoalveolar lavage fluid (BALF) were used as indicators of pulmonary mast cell activation. BALF was obtained before and after endobronchial allergen challenge and assessed for mediator content and cell composition in 4 subject groups: nonatopic nonasthmatics (Group 1, n = 7), nonatopic asthmatics (Group 2, n = 3), atopic nonasthmatics (Group 3, n = 7), and atopic asthmatics (Group 4, n = 7). Before challenge, histamine concentrations were not different between the 4 groups, whereas tryptase concentrations were significantly greater in the atopic asthmatics than in each of the other groups (p less than 0.04). Allergen challenge in atopic asthmatics resulted in significant increases above baseline in mean +/- SD histamine (0.7 +/- 7.1 to 2.8 +/- 2.0 ng/ml) and tryptase (2.0 +/- 1.7 to 10.1 +/- 8.2 ng/ml) concentrations in BALF (p less than 0.03). Atopic nonasthmatics also had increases above baseline in histamine (0.2 +/- 0.2 to 1.2 +/- 1.4 ng/ml) and tryptase (0.5 +/- 0.4 to 1.4 +/- 1.03 ng/ml) concentrations after allergen challenge (p less than 0.05). Though the histamine values were not significantly different between atopic nonasthmatics and atopic asthmatics after allergen challenge, tryptase concentrations were markedly higher in the atopic asthmatic group. The numbers, as well as the predominance of the T mast cell type in atopic asthmatics and nonasthmatics, were no different from controls. In nonatopic subjects, regardless of asthmatic state, histamine or tryptase concentrations were not altered by allergen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Increased concentrations of leukotrienes in bronchoalveolar lavage fluid of patients with ARDS or at risk for ARDS.

The sulfidopeptide leukotrienes (LT) C4 and D4 have been reported to promote the formation of pulmonary edema when administered into the pulmonary circulation of laboratory animals. As a first step in the evaluation of the hypothesis that these leukotrienes participate in the edema formation of the adult respiratory distress syndrome (ARDS), we investigated whether LTC4 and LTD4 were present in the bronchoalveolar lavage (BAL) fluid of patients with ARDS compared to nonsmoker control subjects and to patients with acute respiratory failure exhibiting no radiographic evidence of widespread pulmonary infiltrates but having a clinical predisposition for developing ARDS, i.e., the "at risk" group. Bronchoscopic lavage was performed with sterile 0.9% NaCl on 32 control subjects, nine patients with ARDS, and nine patients "at risk" for ARDS. Leukotrienes were measured in BAL fluid by radioimmunoassay after methanol extraction and HPLC purification of a 20-ml aliquot of the BAL sample. LTC4 and LTD4 (mean +/- SE) increased from 1.1 +/- 0.2 and 1.2 +/- 0.5 ng/lavage in the BAL fluid of control subjects to 6.3 +/- 2.3 and 20.1 +/- 5.9 ng/lavage in patients "at risk" for ARDS and to 12.5 +/- 3.0 and 30.5 +/- 7.8 ng/lavage in patients with ARDS, respectively. The sulfidopeptide LTs correlated with BAL fluid protein content. These results suggest that increased amounts of LTs in BAL fluid are a general finding in patients with ARDS and those "at risk" for ARDS.

Acute Disease↗
PubMed1988

Macrophage spreading disparity: alveolar vs peritoneal.

Macrophage spreading over glass surfaces is a recognized in vitro manifestation of activation. We examined macrophage spreading using a simplified assay. Hartley guinea pigs (n = 15) were anesthetized with pentobarbital (0.4 mg/gm) IM. Macrophages were obtained by lavaging the peritoneal (PM) and alveolar (AM) spaces with sterile 0.9% NaCl (NS). AM or PM (150,000 cells) were placed into chambers of Lab-Tek microtiter slides +/- phorbol myristate acetate (PMA). Slides were incubated /37 degrees C in 5% CO2 for 20 minutes. Macrophages with a diameter greater than 2 x control cells were considered spread. Compared to PM, resident AM show increased spontaneous spreading (16 +/- 2% vs 79 +/- 2%) respectively. AM demonstrated no significant concentration-dependent response to PMA stimulation. The PM has served as the basis for much of the morphological and functional observations attributed to macrophages in general. The above spreading data support the concept of disparity of macrophage function dependent upon various factors, including site of origin. Our observations suggest that extrapolation of macrophage characteristics to cells from discordant sources may not be possible.

Animals↗
PubMed1988

Bronchoalveolar lavage in an animal model of acute lung injury. Relationship between enhanced membrane permeability and transvascular neutrophil flux.

Results of studies utilizing bronchoalveolar lavage (BAL) have led workers to propose that the neutrophil serves as the pivotal cellular element responsible for promoting enhanced alveolar capillary membrane (ACM) permeability in certain forms of acute lung injury. The authors performed BAL on anesthetized, intubated, instrumented sheep before and after the administration of 15 mg/kg ethchlorvynol, a known pulmonary edemagenic agent. Bronchoalveolar lavage fluid (BALF) protein content increased from 0.62 +/- 0.05 to 1.5 +/- 0.15 mg/ml, and the percentage of neutrophils recovered from 2% +/- 1% at baseline to 35% +/- 7% (P less than 0.01) 60 minutes after infusion of ethchlorvynol. After ethchlorvynol infusion into neutropenic sheep (less than 500 cells/microliter), BALF protein content increased from 0.35 +/- 0.08 to 1.5 +/- 0.69 mg/ml (P less than 0.01) with no increase in BALF neutrophil count. In 3 non-neutropenic sheep BAL was performed at 15 and 30 minutes after ethchlorvynol infusion. BALF protein content increased significantly within 15 minutes, whereas the percentage of neutrophils did not change. These findings suggest coexistent ACM injury as reflected by increases in BALF protein content and increased number of neutrophils in BALF does not necessarily imply a cause-and-effect relationship in certain forms of acute lung injury.

Acute Disease↗
PubMed1987

Increase of rat pulmonary microvascular permeability to albumin by recombinant interleukin-2.

Immunotherapy with the lymphokine interleukin-2 (IL-2), with or without lymphokine activated killer (LAK) cells, offers a new approach to the treatment of solid tumors. Unfortunately, most patients receiving IL-2 and LAK cells develop a "third space syndrome" from a presumed generalized increase of vascular permeability. We have investigated the role of IL-2 on lung fluid balance, by measuring changes in lung water and albumin intake. Rats were injected with IL-2 500,000 U i.p. three times a day for 1 to 4 days. At the completion of the injections, lungs were isolated and perfused, and total lung water (TLW) and 125I-albumin uptake were measured. After 1 day of injections, TLW increased from 4.90 +/- 0.14 to 5.57 +/- 0.34 ml/g dry lung and albumin uptake nearly doubled from 0.47 +/- 0.08 to 0.91 +/- 0.28 cm3/s/g dry lung X 10(-3). Longer injection periods increased both TLW and albumin uptake further. After 2 days, TLW and albumin uptake were also significantly increased by 160,000 U i.p. three times a day, but not by 40,000 or 10,000 U. To eliminate possible contributions to increased permeability by (a) LAK cells generated in vivo, or (b) circulating leukocytes, we isolated lungs from normal rats and perfused them for 5 min with a cell-free perfusate containing IL-2 (2, 10, or 5 X 10(-3) U/ml) excipient or 0.9% NaCl placebo. TLW was similar in all groups, but albumin uptake was significantly increased by 10,000 and 50,000 U/ml (0.94 +/- 0.15 and 0.82 +/- 0.16 cm3/s/g dry lung X 10(-3), respectively), but not by 2,000 U/ml. We conclude that lung microvascular albumin permeability is increased following administration of IL-2 in vivo and in vitro. We suggest that LAK cells are not required for the initiation of increased permeability and that IL-2 may have some direct effect on the pulmonary microvasculature.

Albumins↗
PubMed1987

The adult respiratory distress syndrome. Cell populations and soluble mediators in the air spaces of patients at high risk.

In order to better understand the modulation of polymorphonuclear neutrophil influx into the lung during the development of the adult respiratory distress syndrome (ARDS), we evaluated bronchoalveolar lavage fluids from control subjects (n = 9), patients at high risk of developing ARDS (n = 12), and patients with ARDS (n = 11) for cellular and protein content and capacity to promote neutrophil adhesion to tissue culture plastic. Analysis of the lavage fluids from high risk patients and patients with ARDS showed an 8- to 10-fold increase in the total number of cells, an increase in the percentage of neutrophils present (control subjects = 1 +/- 0.4%, high risk = 53 +/- 8%, ARDS = 70 +/- 7%), and a 10- to 40-fold increase in protein content. The adherence of normal neutrophils to plastic surfaces after pretreatment with either concentrated lavage fluid, ultrafiltrates of BALF, or plasma samples was determined to evaluate the neutrophil adherence-promoting activity of each. Lavage fluid from high risk patients and patients with ARDS promoted an approximate 3-fold increase in neutrophil adherence when compared with control lavage fluid. Neutrophil adhesion-promoting activity of the plasma and lavage filtrates (mw less than 500 daltons) was not significantly different from that of control subjects. The adherence-promoting activity found in ARDS lavage was stable at 56 degrees C for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Crossed immunoelectrophoretic analysis of ARDS lavage proteins.

Serum proteins in normal and ARDS bronchoalveolar lavages were analyzed using crossed immunoelectrophoresis. Normal lavages demonstrated relatively few proteins (albumin, alpha 1-antitrypsin, transferrin, and haptoglobin) in low concentrations. In contrast, substantial amounts of all identifiable serum proteins were detected in ARDS lavages. IgA was apparently locally produced. Two of the largest proteins, beta-lipoprotein (mol wt greater than 2 million) and IgM (mol wt approximately 900,000) were found to be complexed as evidenced by their coprecipitation in a single spike in ARDS lavage. Electrophoretic modifications of ARDS albumin and alpha 1-antitrypsin precipitation peaks and partial identity spurring of the alpha 1-lipoprotein peak with other precipitation loops indicated possible complex formation between these proteins and other possibly pathogenic lung fluid constituents. Similarly, modifications of orosomucoid and Gc-globulin peaks indicated possible molecular alterations resulting from interactions with other components. The relatively few protein modifications exhibited in ARDS lavages together with alpha 1-antitrypsin-protease complex formation confirm the relative absence of substantial proteolytic activity in ARDS edema fluids obtained within 12 hr of the onset of the syndrome demonstrated in previous studies.

Albumins↗
PubMed1986

Increased pulmonary artery pressure in association with Raynaud's phenomenon.

Pulmonary artery vasospasm is a hypothesized antecedent and etiologic factor in the pulmonary hypertension associated with progressive systemic sclerosis. Recent clinical data refute the existence of pulmonary vasospasm in a cohort of patients with scleroderma and normal baseline pulmonary artery pressure. A case of episodic pulmonary hypertension associated with a digital Raynaud's response is reported, and a cardiac mechanism is hypothesized.

Adult↗
PubMed1986

Adult respiratory distress syndrome: causes, morbidity, and mortality.

The increased microvascular permeability of the adult respiratory distress syndrome (ARDS) results in multiple organ injury with the lungs and subsequently the kidneys as the principal targets. Direct pulmonary injury, for example aspiration of gastric contents, and indirect injury, for instance abdominal sepsis, can lead to the syndrome. The predominant infectious cause of the syndrome is gram-negative aerobic rods. Even in patients with noninfectious causes of the syndrome, the incidence of subsequent pneumonia and sepsis with gram-negative aerobic rods is high so that these organisms contribute greatly to the morbidity and mortality that result from the syndrome. Activation of polymorphonuclear leukocytes and platelets and proteolysis of complement and coagulation components contribute to the pathogenesis of the syndrome, particularly from the indirect or blood-borne causes. Therapy is largely supportive and has not progressed substantially since the introduction of positive end expiratory pressure with mechanical ventilation. The outlook for recovery of lung function of survivors is generally good, but only one in three with the syndrome survives. Because of the inflammatory properties of the syndrome, current interest for therapy centers on parenteral use of nonsteroidal antiinflammatory agents and prostaglandins of the E and I series.

Animals↗
PubMed1985

Intravenous nitroglycerin-induced intracranial hypertension.

Nitroglycerin therapy can cause dose-related increases in intracranial pressure. Rare cases of neurologic sequelae attributed to nitroglycerin have appeared in the literature. We report such a case, in which symptoms completely resolved after cessation of nitroglycerin therapy. Widespread use of high-dose iv nitroglycerin makes knowledge of this effect important for all practitioners.

Female↗
PubMed1985

Adult respiratory distress syndrome. Prognosis after onset.

In 88 patients with the adult respiratory distress syndrome, clinical, laboratory, cardiopulmonary, and demographic data collected on the day of onset of the syndrome were used to identify predictors of survivorship and mortality. Variables that individually were associated with mortality were then analyzed simultaneously by the Cox proportional hazards function and by multiple discriminant function using a step-up procedure. Four variables taken singly were significantly associated with mortality. These were the presence of less than 10% band forms on the initial peripheral blood smear, persistent acidemia with arterial pH less than 7.40, calculated HCO-3 less than 20 mg/dl, and blood urea nitrogen greater than 65 mg/dl. After eliminating those variables that did not contribute significantly to mortality in the presence of the others, only low band forms, low pH, and low HCO-3 were significantly associated with increased mortality. These findings illustrate the continued high mortality rate in the syndrome and indicate possible systemic aberrations that contribute to its severity.

Adult↗
PubMed1985

Chemotactic activity in bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome.

Recent studies have shown that an influx of polymorphonuclear neutrophils into distal air spaces occurs early in the adult respiratory distress syndrome (ARDS). To study the mechanism of cell accumulation in this syndrome, we have evaluated the chemotactic activity in bronchoalveolar lavage fluid from patients with ARDS. Lavage fluid was obtained from 16 patients with ARDS within 24 h of endotracheal intubation and from 5 normal nonsmoking subjects. Lavage fluid from patients with ARDS had an average of 85% neutrophils on differential counts of cytologic preparations compared to less than 3% neutrophils for the control subjects. After removal of cells and lipids, lavage fractions of molecular weight greater than 10,000 daltons were chemotactic for human neutrophils in 14 of 16 patients, but no activity was seen with the normal lavages. Preliminary studies to identify the chemotactic factor were performed.

Adult↗
PubMed1984

Development of the adult respiratory distress syndrome: progressive alteration of neutrophil chemotactic and secretory processes.

Chemotaxis and lysosomal enzyme release in peripheral blood neutrophils taken from patients before, during, and after recovery from the adult respiratory distress syndrome (ARDS) were studied. This allowed for correlation of cellular function with changes in a patient's clinical status. It was found that neutrophils from 8 of 9 patients with the fully developed syndrome exhibited a profound depression of chemotaxis (63% depressed, P = 0.0001) and a fourfold elevation of basal lysosomal enzyme release relative to neutrophils from healthy controls (P = 0.0001). These findings of depression of chemotaxis and enhanced basal enzyme release were also detected in neutrophils taken from 7 of 11 patients in whom clinical risk factors (eg, sepsis, pneumonia) for the syndrome had developed. Following resolution of the adult respiratory distress syndrome, the above changes in neutrophil function resolved in the four patients studied during convalescence. Healthy neutrophils exposed to plasma samples (untreated or zymosan-activated) from control subjects and patients with ARDS could not be distinguished with respect to chemotaxis and enzyme secretion. It is concluded that patients in whom ARDS develops show profound but reversible changes in peripheral neutrophil activity which can be measured following the development of a clinical predisposition for the syndrome. Further, the presence of a humoral substance capable of promoting chemotaxis or enzyme secretion from healthy neutrophils in the untreated plasma of patients suffering from ARDS was not demonstrated. This suggests that alteration of neutrophil activity measured in patients with the fully developed syndrome may be cellular in origin.

Acetylglucosaminidase↗