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Biomedical subjects

J A Cooper

Publications and source records attributed to J A Cooper.

At least 343 records · Page 19Linked to original sources
PubMed1986

Drug-induced pulmonary disease. Part 1: Cytotoxic drugs.

Numerous pharmacologic agents used in the treatment of cancer have been linked to pulmonary toxic side effects. Mechanisms of damage by these drugs include direct pulmonary toxicity and indirect effects through enhancement of inflammatory reactions. Risk factors for development of pulmonary damage have been elucidated for some agents but they remain unclear for others. Clinical features are similar for most categories of cytotoxic agents, and the most common associated clinical syndrome is chronic pneumonitis/fibrosis. Treatment and outcome vary with each particular agent. In Part 1 of this review, clinical aspects and pathogenic mechanisms of cytotoxic drug-induced pulmonary disease are discussed.

Aging↗
PubMed1986

Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs.

Nonchemotherapeutic drugs may also cause pulmonary parenchymal alterations. Mechanisms of pulmonary damage by these agents are diverse and may involve alterations of pulmonary homeostasis. Clinical features of noncytotoxic, drug-induced pulmonary disease are more heterogeneous than those associated with cytotoxic drugs, and several clinical syndromes are equally represented. Treatment and outcome vary with each individual drug and clinical presentation. In part 2, clinical and pathogenic aspects of noncytotoxic, drug-induced pulmonary disease are discussed.

Anti-Arrhythmia Agents↗
PubMed1986

Cyclophosphamide modulation of bronchoalveolar cellular populations and macrophage oxidative metabolism. Possible mechanisms of pulmonary pharmacotoxicity.

Cyclophosphamide, an immunosuppressive alkylating agent, has been reported to cause acute and chronic pulmonary injury in both humans and animals. Cyclophosphamide is also a common component of multi-drug regimens that show high pulmonary toxic potential. Although mechanisms of pulmonary damage caused by cyclophosphamide or other cytotoxic agents are unknown, possibilities include direct toxicity to pulmonary tissue or indirect toxicity through activation of pulmonary inflammatory cells. We report here a model system for the study of acute effects of cyclophosphamide on pulmonary immune cells in rats. Our findings show that 16 h after 1 intraperitoneal dose of cyclophosphamide there is: a dose dependent release of locally produced low molecular weight chemotactic factors for blood monocytes into bronchoalveolar lavage (BAL) fluid, a pulmonary influx of immature myeloperoxidase positive macrophages in low dose cyclophosphamide treated animals, an enhancement of oxidant generation by pulmonary macrophages from low dose treated animals that correlates with the presence of myeloperoxidase positive macrophages, the presence of factors in BAL fluid of treated rats that modulate oxidant release by normal rat pulmonary macrophages, a dose dependent reduction in the percentage of BAL lymphocytes, and evidence for pulmonary injury as manifested by elevated BAL fluid albumin concentrations in low dose cyclophosphamide treated animals. These findings suggest that cyclophosphamide may induce pulmonary injury through activation of pulmonary immunocompetent cells and subsequent attraction of systemic inflammatory cells.

Albumins↗
PubMed1986

Pulmonary epithelial clearance of 99mTc-DTPA after thrombin-induced pulmonary microembolism.

We investigated the effect of thrombin-induced pulmonary microembolism on the pulmonary clearance rate of aerosolized 99mTc diethylenetriamine pentaacetic acid (99mTc-DTPA) in awake, chronically prepared sheep. Chest activity was recorded after administration of a 0.44 micron aerosol of 99mTc-DTPA. Decay-corrected data were fit to an exponential and expressed as percent decrease per min (%/min). Sheep were given alpha-thrombin intravenously (80 U/kg for 10 min) 60 min after the aerosol administration. The clearance rate prior to alpha-thrombin was 0.35 +/- 0.05 %/min (mean +/- SEM). During alpha-thrombin administration, the clearance rate increased to 5.84 +/- 0.70 %/min (p less than 0.001 from baseline), but returned to 0.41 +/- 0.06 %/min within 30 min after the end of the thrombin infusion. The increased clearance rate during alpha-thrombin administration was not due to increased lung volume since alpha-thrombin did not change functional residual capacity. Moreover, the clearance rate was unchanged during gamma-thrombin administration, which does not induce coagulation, or during alpha-thrombin challenge in defibrinogenated animals. alpha-thrombin administration in neutrophil-depleted sheep caused a transient increase in DTPA clearance similar to that in control sheep, suggesting that the increase occurred independently of neutrophils. The results indicate that alpha-thrombin causes a large, transient increase in 99mTc-DTPA clearance, which may be the result of increased epithelial permeability. This response is dependent on the activation of intravascular coagulation.

Aerosols↗
PubMed1986

The relationship between bronchoalveolar neutrophil recruitment and bronchoconstriction induced by a soluble extract of cotton bracts.

Byssinosis is characterized by an obstructive bronchitis in some workers exposed to cotton dust. Mechanisms of airway alterations induced by cotton dust are unknown. To study mechanisms of these alterations, we administered an aqueous extract of cotton bract (CBE) to normal human subjects. After CBE inhalation, we demonstrated reproducible reductions in flow rates of variable magnitude. The percentage of polymorphonuclear leukocytes (PMN) recovered by bronchoalveolar lavage (BAL) and total PMN per milliliter BAL fluid were increased after challenge with CBE, and these parameters were correlated (r = 0.556 and r = 0.553, respectively) with the degree of bronchoconstriction induced by CBE. In addition, chemotactic factors for PMN were noted in BAL fluid and in supernatant from BAL cell cultures. The degree of BAL fluid chemotactic activity correlated with the degree of bronchoconstriction induced by CBE. Assessment of molecular sieve column effluent demonstrated BAL fluid to have 3 distinct peaks of chemotactic activity (approximate molecular weight, greater than 25,000, 10,000, and less than 1,000 daltons) and cell culture supernatant to contain 1 peak (approximate MW, 10,000 daltons). Complement activation as one source of BAL chemotactic activity was suggested by almost complete inhibition of BAL chemotactic activity after incubation with antibody to the fifth component of complement (C5) and detection of C5a des Arg in BAL fluid from some subjects challenged with CBE. These findings suggest that exposure of volunteer subjects to CBE results in a bronchoalveolar inflammatory response related to both complement activation and chemotactic factor synthesis by luminal cells.

Adult↗
PubMed1986

Biologic activity of purified cotton bract extracts in man and guinea pig.

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

Adolescent↗
PubMed1986

Vegetable dust and airway disease: inflammatory mechanisms.

Exposure to cotton or grain dust causes an obstructive bronchitis in certain subjects, mechanisms of which are poorly understood. A difficulty encountered in discerning mechanisms of this airway disease is the lack of knowledge of the active components of these dusts. Clinical features suggest common but not exact mechanisms of the airway disease associated with these vegetable dusts. Human and animal studies show evidence of acellular and cellular inflammatory mechanisms of the bronchoconstriction and inflammation associated with these disorders. Potential cellular sources include alveolar macrophages, polymorphonuclear leukocytes, mast cells, basophils, eosinophils and lymphocytes. Acellular origins include the complement and humoral antibody systems, both of which have been implicated, although their pathogenic role in grain or cotton dust disorders is uncertain. In this review we critically address potential inflammatory mechanisms of airway alterations resulting from cotton or grain dust exposure. General mechanisms of bronchoconstriction are first presented, then specific studies dealing with either of the two dusts are discussed. We believe this area of research may be fruitful in dissecting mechanisms of bronchoconstriction and airway inflammation, especially as more human studies are undertaken.

Animals↗
PubMed1986

Acquisition of gamma camera and physiological data by computer.

We have designed, implemented, and tested a new Research Data Acquisition System (RDAS) that permits a general purpose digital computer to acquire signals from both gamma camera sources and physiological signal sources concurrently. This system overcomes the limited multi-source, high speed data acquisition capabilities found in most clinically oriented nuclear medicine computers. The RDAS can simultaneously input signals from up to four gamma camera sources with a throughput of 200 kHz per source and from up to eight physiological signal sources with an aggregate throughput of 50 kHz. Rigorous testing has found the RDAS to exhibit acceptable linearity and timing characteristics. In addition, flood images obtained by this system were compared with flood images acquired by a commercial nuclear medicine computer system. National Electrical Manufacturers Association performance standards of the flood images were found to be comparable.

Humans↗
PubMed1985

Effect of capping protein on the kinetics of actin polymerization.

Acanthamoeba capping protein increased the rate of actin polymerization from monomers with and without calcium. In the absence of calcium, capping protein also increased the critical concentration for polymerization. Various models were evaluated for their ability to predict the effect of capping protein on kinetic curves for actin polymerization under conditions where the critical concentration was not changed. Several models, which might explain the increased rate of polymerization from monomers, were tested. Two models which predicted the experimental data poorly were (1) capping protein was similar to an actin filament, bypassing nucleation, and (2) capping protein fragmented filaments. Three models in which capping protein accelerated, but did not bypass, nucleation predicted the data well. In the best one, capping protein resembled a nondissociable actin dimer. Several lines of evidence have supported the idea that capping protein blocks the barbed end of actin filaments, preventing the addition and loss of monomers [Cooper, J. A., Blum, J. D., & Pollard, T. D. (1984) J. Cell Biol. 99, 217-225; Isenberg, G. A., Aebi, U., & Pollard, T. D. (1980) Nature (London) 288, 455-459]. This mechanism was also supported here by the effect of capping protein on the kinetics of actin polymerization which was nucleated by preformed actin filaments. Low capping protein concentrations slowed nucleated polymerization, presumably because capping protein blocked elongation at barbed ends of filaments. High capping protein concentrations accelerated nucleated polymerization because of capping protein's ability to interact with monomers and accelerate nucleation.

Actin Depolymerizing Factors↗
PubMed1985

Protein phosphorylation and growth control.

Many growth factor receptors and retroviral transforming proteins share the property of phosphorylating proteins on tyrosine. Several substrates for both types of protein-tyrosine kinase have been identified. Treatment of quiescent cells with growth factors such as EGF and PDGF, whose receptors have ligand-stimulated protein-tyrosine kinase activities, induces tyrosine phosphorylation of three proteins, p45, p42 and p41. Two phosphorylated forms of p42 are found, the more basic of which is present in some but not all cells transformed by viral protein-tyrosine kinases. p42 is rapidly (as early as 1 min) but transiently (decreased to baseline by 2h) phosphorylated following PGDF or EGF treatment of quiescent fibroblasts. At saturating levels of mitogen the stoichiometry of p42 phosphorylation is greater than 50%. p42 is a highly conserved, rare (0.002% of total cell protein), soluble cytoplasmic protein. IGF I and insulin, whose receptors also have ligand-stimulated protein-tyrosine kinase activity, induce p42 phosphorylation in appropriate cells. In the case of insulin this effect has been observed in cells with large numbers of insulin receptors. p42 is also phosphorylated in response to mitogens whose receptors lack protein-tyrosine kinase activity, for example 12-O-tetradecanoylphorbol-13-acetate (TPA) and thrombin. For TPA there is evidence that this is an indirect effect due to the activation of a protein-serine/threonine kinase. On the basis of the highly conserved nature of this response and its generality, it seems likely that tyrosine phosphorylation of p42 is important for at least early responses to mitogens.

Animals↗
PubMed1985

Protein kinase C phosphorylates pp60src at a novel site.

The transforming protein of Rous sarcoma virus (pp60v-src) and its normal cellular homolog (pp60c-src) are demonstrated to be phosphorylated at serine 12 in vivo under certain conditions. We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed.

Amino Acid Sequence↗
PubMed1985

Comparison of technetium-99m pyrophosphate and technetium-99m methylene diphosphonate with variable amounts of stannous chloride in the detection of acute myocardial infarction.

The authors prospectively compared the ability of Tc-99m pyrophosphate (PYP) and Tc-99m methylene diphosphonate (MDP) to detect acute myocardial infarctions. The agents used were PYP (12 mg) with 3.4 mg of stannous chloride, MDP (10 mg) with 1.0 mg of stannous chloride, and MDP (10 mg) with 3.4 mg of stannous chloride. Imaging was performed on three consecutive days on 34 patients with proven myocardial infarctions, using the same agent on the first and third days of the study and an alternate agent on the second day. Agents were assigned randomly to each of six groups of patients. First images were obtained an average of 3.7 days (range, one to six days) following myocardial infarction. Seventeen of 23 patients (75%) had images positive for acute myocardial infarction with Tc-99m PYP, whereas only two of 21 patients (9.5%) had positive studies with Tc-99m MDP with 3.4 mg of stannous chloride and one of 24 patients (4.2%) had positive studies with Tc-99m MDP and 1.0 mg of stannous chloride. All three myocardial infarctions detected by Tc-99m MDP were extensive and transmural. When MDP and PYP were both positive in the same patient, the apparent size of the myocardial infarction was much smaller with the MDP. It is concluded that MDP can detect only large myocardial infarctions, has poor localization in the infarcted tissue, and varying the stannous chloride content of the preparation does not improve the ability of MDP to detect acute myocardial infarctions.

Adult↗