Biomedical subjects
Publications and source records attributed to J A Cooper.
Administration of a number of therapeutic agents is associated with respiratory alterations. Mechanisms of these alterations are unclear but may include both direct toxic effects of the drugs and indirect effects through actions of the drugs on inflammatory cells. This review discusses mechanisms of the varied patterns of drug-induced pulmonary disease.
Airway inflammation is thought to be an important determinant of bronchoconstriction and bronchial hyperreactivity. We have recently demonstrated that bronchoconstriction induced by an aqueous extract of cotton bracts (CBE) is associated with bronchoalveolar complement activation, release of polymorphonuclear neutrophil (PMN) chemoattractants by pulmonary cells, and increased numbers of bronchoalveolar lavage PMN's. In the present study we performed bronchoalveolar lavage (BAL) on subjects after CBE or control (saline) challenge and examined whether BAL cells were activated in vitro to produce other inflammatory agonists. After CBE administration, cultured BAL cells released increased amounts of the reactive O2 species, superoxide (O2-.), and the cyclooxygenase products prostaglandin E2 and thromboxane B2. Although none of these in vitro parameters of BAL cell activation appeared to correlate with the degree of bronchoconstriction induced by CBE, BAL fluid levels of thromboxane B2 were also increased after CBE administration and in vivo amounts of this eicasanoid did correlate with the degree of bronchoconstriction induced by CBE (r = 0.50, P less than 0.04). Finally, although cell culture supernatants were highly chemotactic for PMN's, concentrations of leukotriene B4 were not increased, suggesting other chemotaxins were released by BAL cells in this setting. We conclude that CBE administration activates bronchoalveolar cells to release reactive O2 species and cyclooxygenase products that may be important in the bronchoconstricting response to CBE.
We examined the mechanisms of platelet uptake in the lungs after alpha-thrombin-induced pulmonary microembolism. Platelets labeled with 111In-oxine were reinfused into chronically prepared sheep. Pulmonary microembolism resulted in an increase in lung platelet radioactivity (95.5 +/- 15.3%; n = 4), which was followed by an exponential washout (half-life = 115 +/- 4 min). Platelet uptake in the lungs was more sustained after prior fibrinolytic inhibition with tranexamic acid (half-life = 178 +/- 11 min), although the initial increase was similar (90.7 +/- 9.6%; n = 7). Prior depletion of fibrinogen with ancrod (Arvin), blunted the initial increase in lung platelet uptake after alpha-thrombin challenge (31.7 +/- 11.3%, n = 5), indicating that the effect of thrombin was markedly dependent on fibrinogen. We examined the role of circulating granulocytes, since platelets may bind to subendothelial matrix exposed after granulocyte-mediated lung vascular injury. Maximal pulmonary platelet uptake after thrombin in granulocytopenic sheep was not different from control (71.7 +/- 14.4%; n = 4). The results indicate that pulmonary microembolism results in lung platelet sequestration. Platelet uptake is not dependent on granulocyte-mediated vascular injury but requires fibrin deposition and is sustained if fibrinolysis is inhibited.
We investigated the role of fibrin in the sequestration of neutrophils in lungs challenged with microembolism. Lungs of chronically prepared awake sheep were imaged after infusion of 111In-neutrophils and 131I-fibrinogen. Thrombin (80 units/kg) was administered to induce fibrin sequestration in the lung. One group received tranexamic acid (4 mg/kg i.v.) to inhibit fibrinolysis, and the control group received a saline infusion. Thrombin infusion increased both 131I-fibrinogen and 111In-neutrophils in the lung, but the increases were greater and more prolonged in the fibrinolysis-inhibited group. We examined the adherence of isolated neutrophils to fibrin matrix to investigate how neutrophil-fibrin interactions could mediate neutrophil sequestration. Unstimulated neutrophils showed a 37.5 +/- 3.1% adherence to fibrin in contrast to a 3.9 +/- 0.4% neutrophil adherence to endothelium and a 6.5 +/- 0.5% adherence to agarose. Neutrophil adherence to fibrin increased to 81.7 +/- 6.2% with activation by phorbol myristate acetate (10(-8) M) and was inhibited by a monoclonal antibody directed against the beta-chain of the CD18 leukocyte adhesion glycoprotein. The findings indicate that retention of pulmonary fibrin microthrombi is associated with increased lung uptake of neutrophils. Fibrin serves as a substrate for neutrophil adherence, and this adherence is mediated by expression of the CD18 glycoprotein complex on neutrophils. Fibrin sequestration in the lung may contribute to lung vascular injury by inducing pulmonary neutrophil uptake.
In the present work, the hypothesis that individuals naturally exposed to Plasmodium falciparum malaria infection in endemic areas produce antibodies directed against non-repetitive epitopes of the circumsporozoite protein was investigated. Using a synthetic peptide reproducing the non-repetitive group-conserved region I sequence, we have shown that specific anti-region I antibodies are detectable in sera from endemic countries. Of these sera, 87% also had antibodies against the immunodominant repetitive epitope (Asn-Ala-Asn-Pro, NANP) of P. falciparum. In order to study the immunogenicity of this non-repetitive epitope, a synthetic peptide consisting of both region I and three (NANP) repeats [RI-(NANP)3] was used to immunize inbred strains of mice. H-2b mice produced antibodies against both the repetitive and the non-repetitive epitope. These antibodies were specific for each epitope, recognized P. falciparum sporozoites in immunofluorescence, and inhibited sporozoite penetration into human liver cells in vitro. Non-H-2b mice were completely unresponsive. Lymph node cells from H-2b mice immunized with RI-(NANP)3 peptide proliferated in the presence of RI-(NANP)3 and of (NANP)4 peptide, but never in the presence of RI peptide alone. These findings demonstrate that in the configuration used (i) the non-repetitive epitope region I does not carry T-helper epitopes; (ii) the (NANP) repetitive epitope may act as a carrier for the immune response to region I in mice; and (iii) therefore, immune response to region I in man probably depends on the recognition of T-cell epitopes similar to those involved in the anti-NANP response: i.e. such a T epitope may be NANP itself in responding individuals or another, not yet recognized, sporozoite T-cell epitope.
The authors examined the in vitro effects of serum generated by the action of alpha-thrombin on citrated whole blood or plasma. Serum samples were assessed for their ability to induce neutrophil aggregation, neutrophil adherence to cultured endothelial cell monolayer, and superoxide anion generation. The results indicated that both blood- and plasma-derived sera induced similar increases in neutrophil aggregation. Both sera also induced neutrophil adherence to cultured bovine pulmonary artery endothelial monolayer. The adherence increased in a time-dependent manner, producing little change after 5 minutes, and reached maximal response at 60 minutes. Full potency of the neutrophil adherence was evident with serum samples obtained after clotting time of 20 minutes but not at 5 minutes clotting time. The adherence-inducing activity of serum was gradually lost after storage at -20 C and was abolished by 100 C treatment for 2 minutes. In contrast, heating serum to 56 C for 30 minutes did not alter the adherence-inducing activity. Both ether and aqueous fractions obtained after ether extraction of serum possessed adherence-promoting activities, indicating that multiple factors (both lipid and water soluble) were involved. Pretreatment of the endothelium with serum resulted in increased endothelial adhesiveness, but the serum pretreatment failed to induce adhesiveness to subendothelial matrix, indicating that endothelial cells play an active role in acquiring the adhesive property. Serum obtained from thrombin-generated whole blood also resulted in a modest degree of neutrophil superoxide anion generation, but this did not occur with plasma-derived serum. The results indicate that serum factors obtained by clotting blood with thrombin induce neutrophil aggregation and neutrophil adherence to the endothelium as well as superoxide production. These factors appear to be generated in the plasma phase, because the responses were similar in blood- and plasma-derived serum.
Two procedures for providing the synchronization of ventilation scintigraphic data to create dynamic displays of the pulmonary cycle are described and compared. These techniques are based on estimating instantaneous lung volume by pneumotachometry and by scintigraphy. Twenty-three patients were studied by these two techniques. The results indicate that the estimation of the times of end-inspiration and end-expiration are equivalent by the two techniques but the morphologies of the two estimated time-volume waveforms are not equivalent. Ventilation cinescintigraphy based on time division gating but not on isovolume division gating can be equivalently generated from list mode acquired data by employing either technique described.
Angina and ischemic electrocardiographic changes occurred after administration of oral dipyridamole in four patients awaiting urgent myocardial revascularization procedures. To our knowledge, this has not previously been reported as a side effect of preoperative dipyridamole therapy, although dipyridamole-induced myocardial ischemia has been demonstrated to occur in animals and humans with coronary artery disease. Epicardial coronary collateral vessels were demonstrated in all four patients; a coronary "steal" phenomenon may be the mechanism of the dipyridamole-induced ischemia observed.
We examined the selectivity of the bovine pulmonary artery endothelial monolayer in vitro to molecules of different sizes. The cultured bovine pulmonary endothelial monolayer was grown on a gelatinized filter and the transendothelial transport was studied by determining the permeability of molecules ranging from 182 to 340,000 daltons under diffusion conditions. The permeabilities across the cultured bovine endothelium were modeled according to cylindrical pore theory. The data were best fit by a two-pore model with radii 65 A and 304 A and a ratio of small to large pores of 160:1. The results indicate that the cultured endothelial monolayer is a selective barrier to molecules of different sizes and that the molecular selectivity is consistent with a diffusional pathway through endothelial pore equivalents. The cultured endothelial monolayer is a useful system for studying the permeability characteristics of the endothelial barrier.
Administration of more than 40 separate pharmacologic agents has been associated with some form of pulmonary toxicity. This problem is becoming more significant every year. Occasionally, effective modes of therapy must be withdrawn because of undesirable pulmonary side effects, putting patients at risk for potentially lethal diseases. Pulmonary parenchymal damage due to drugs is an especially troublesome problem because irreversible pulmonary disease may occur. Mechanisms of pulmonary parenchymal tissue damage by drugs are unclear. It appears that some drugs induce direct tissue injury in addition to indirect tissue damage through amplification of pulmonary inflammation; other drugs cause pulmonary alterations solely through indirect mechanisms. Common clinical syndromes associated with drug-induced pulmonary parenchymal disease include pneumonitis/fibrosis, hypersensitivity lung disease, and noncardiogenic pulmonary edema. Less common patterns of pulmonary parenchymal injury by drugs include bronchiolitis obliterans and a pulmonary renal syndrome. Risk factors for pulmonary injury due to pharmacologic agents are partially defined but not entirely understood. To date, there are no adequate tests for early detection of pulmonary damage by drugs, although research into this area is active. This review discusses mechanisms and clinical features of drug-induced pulmonary parenchymal injury to aid the clinician in recognizing and understanding these syndromes.
Fifteen children and adolescents with a history of acquired aphasia were administered a battery of language and academic tests, 1-10 years postonset. As a group, these children performed significantly more poorly than non-brain-injured subjects on the language measures, with deficits in word, sentence, and paragraph comprehension; naming; oral production of complex syntactic constructions; and word fluency. One particular language deficit or cluster of deficits did not characterize the group as a whole. For individual brain-injured subjects, language deficits ranged from no or only mild impairment to significant language deficits. All brain-injured subjects were functional verbal communicators at the time of the study; that is, all were oral and primarily used grammatical sentences as their means of communication. Academic difficulties were characteristic of this population. Two thirds of the brain-injured group were receiving academic assistance of some kind at the time of the study. Poor performance on arithmetic calculations was typical. The brain-injured group was heterogeneous with regard to age at onset, etiology, extent of damage, length of recovery, and outcome profiles. Careful and comprehensive assessment of a range of language and academic abilities is essential to adequately identify needs and appropriate intervention strategies for this population.
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Gelsolins are actin-binding proteins that cap, nucleate, and sever actin filaments. Microinjection of cytoplasmic or plasma gelsolin into living fibroblasts and macrophages did not affect the shape, actin distribution, deformability, or ruffling activity of the cells. Gelsolin requires calcium for activity, but the NH2-terminal half is active without calcium. Microinjection of this proteolytic fragment had marked effects: the cells rounded up, stopped ruffling, became soft, and stress fibers disappeared. These changes are similar to those seen with cytochalasin, which also caps barbed ends of actin filaments. Attempts to raise the cytoplasmic calcium concentration and thereby activate the injected gelsolin were unsuccessful, but the increases in calcium concentration were minimal or transient and may not have been sufficient. Our interpretation of these results is that at the low calcium concentrations normally found in cells, gelsolin does not express the activities observed in vitro at higher calcium concentrations. We presume that gelsolin may be active at certain times or places if the calcium concentration is elevated to a sufficient level, but we cannot exclude the existence of another molecule that inhibits gelsolin. Microinjection of a 1:1 gelsolin/actin complex had no effect on the cells. This complex is stable in the absence of calcium and has capping activity but no severing and less nucleation activity as compared with either gelsolin in calcium or the NH2-terminal fragment. The NH2-terminal fragment-actin complex also has capping and nucleating activity but no severing activity. On microinjection it had the same effects as the fragment alone. The basis for the difference between the two complexes is unknown. The native molecular weight of rabbit plasma gelsolin is 82,500, and the extinction coefficient at 280 nm is 1.68 cm2/mg. A new simple procedure for purification of plasma gelsolin is described.
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The three types of physicians being educated in the People's Republic of China--practitioners in traditional Chinese medicine, traditional Mongolian medicine, and western-type medicine--and the nation's medical schools are discussed. The country officially recognizes 117 health professions educational institutions--23 colleges of traditional Chinese medicine, 91 western-type medical schools, two schools of pharmacy, and one institution that trains pharmacy, medical, and hygienic inspectors. Eight of the 91 western-type schools, in addition to providing training in western-type medicine, also offer education in traditional Chinese medicine. Training in Mongolian medicine is offered by one of these eight western schools and by one other western school. No schools offer only Mongolian medicine education.
We have developed an experimental system to measure the permeability of the cultured endothelial monolayer. The luminal-to-abluminal flux of 125I-albumin across cultured pulmonary endothelium was expressed as a clearance rate equal to the permeability-surface area product. After clearance rate measurement for a 30-min base-line period, a test agent was added to the luminal side, and the clearance rate was remeasured during a 30-min experimental period. In control studies the base-line clearance rate was 0.343 +/- 0.017 microliter/min. After correction for the diffusional resistances of the filter and unstirred layers, the calculated permeability of the endothelial monolayer was 1.2 X 10(-5) cm/s. When culture medium was the test agent, the experimental clearance rate was unchanged from the base-line value. After addition of 4 mM oleic acid to the luminal chamber, the clearance rate was 0.528 +/- 0.017 microliter/min compared with a base-line value of 0.330 +/- 0.008 microliter/min (P less than 0.005). This method allows the calculation of endothelial permeability with correction for unstirred layers and the use of each monolayer as its own control.
We investigated the dose-response effect of positive end-expiratory pressure (PEEP) and increased lung volume on the pulmonary clearance rate of aerosolized technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Clearance of lung radioactivity was expressed as percent decrease per minute. Base-line clearance was measured while anesthetized sheep (n = 20) were ventilated with 0 cmH2O end-expiratory pressure. Clearance was remeasured during ventilation at 2.5, 5, 10, 15, or 20 cmH2O PEEP. Further studies showed stepwise increases in functional residual capacity (FRC) (P less than 0.05) measured at 0, 2.5, 5, 10, 15, and 20 cmH2O PEEP. At 2.5 cmH2O PEEP, the clearance rate was not different from that at base line (P less than 0.05), although FRC was increased from base line. Clearance rate increased progressively with increasing PEEP at 5, 10, and 15 cmH2O (P less than 0.05). Between 15 and 20 cmH2O PEEP, clearance rate was again unchanged, despite an increase in FRC. The pulmonary clearance of aerosolized 99mTc-DTPA shows a sigmoidal response to increasing FRC and PEEP, having both threshold and maximal effects. This relationship is most consistent with the hypothesis that alveolar epithelial permeability is increased by lung inflation.
Many healthy subjects who have had no exposure to cotton textile dusts will experience significant reductions in expired flow rate following an inhalational challenge with an aqueous extract of cotton bracts (CBE). Differences noted among individuals in the magnitude of the bronchial response to a standardized preparation of CBE suggest variable airway reactivity. The mechanism of this response and the reasons for its variability among these naive subjects are unknown. We have studied this problem by performing bronchoalveolar lavage on 13 volunteer subjects with no history of textile dust exposure. Two to three months later, a bronchial provocation with aqueous CBE was performed by an investigator blinded to the lavage results. Subjects with greater than 20 percent drop in flow rate at 40 percent of vital capacity during a partial forced expiration (MEF 40 percent [P]) following CBE had a reduction in total recoverable alveolar macrophages, with a resultant increase in the percentage of recoverable lymphocytes. The magnitude of response (MEF 40 percent [P]) correlated directly with the measured lymphocyte percentage (r = 0.69 p less than 0.01) and inversely with the total numbers of recovered cells.