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Fou -", + "Densed", + "\"10 KANT NTREET", + "as too", + "NRW YORK. N.Y. 10032", + "and too much", + "(212)", + "of projects", + "weil", + "Application for Research Gront", + "(Use exiro pages os needed)", + "12-15-78", + "1. Principal Investigator (give title and degrees):", + "John E. Repine, MD", + "John R. Hoidal,MD", + "Assistant Director, Webb-Waring", + "and", + "Assistant Professor of", + "Lung Institute", + "Medicine", + "Associate Professor of Medicine", + "2. Institution & address:", + "Univerisity of Colorado Medical Center", + "4200 East Ninth Avenue", + "Denver, Colorado, 80262", + "3. Department(s) where reseorch will be done or colloboration provided.", + "Webb-Waring Lung Institute", + "and", + "Department of Medicine", + "4. Shorl title of study:", + "The Role of Phagocytes in the Development of Centrilobular Emphysema", + "5. Proposed starting date:", + "July 1,1979.", + "6. Estimated time to complete:", + "one year", + "7. Brief description of specific research aims:", + "(1.) To determine whether there are differences in the abilities of lung phagocytes", + "from human cigarette smokers and nonsmeking control subjects to make factors", + "which attract monocytes and/or neutrophils.", + "(2.) To determine whether there are differences in the oxygen(o,) uptake, super-", + "oxide anion(0, ), hydrogen peroxide(H,0, hydroxyl radicaI(.OH), superoxide", + "dismutase (sob) and catalase activities of the lung phagocytes from human", + "cigarette smokers and nonsmokers.", + "(3.) To determine whether alterations in the numbers and/or biochemical activities", + "of lung phagocytes affect the development of centrilobular emphysema (CLE)", + "a", + "using chronic cadmium chloride(CdC1,) induced CLE in the rat as a model of", + "suitable rn'", + "I CLE seen in human cigarette smokers.", + "&s' melity", + "The leag tchm goal of the project is to determine the role of lung phagocytes", + "in", + "the develcoment of the CLE which is very frequently found in individuals who", + "smoke cigarettes. If we can determine a relationship between cigarette smoking,", + "the numbers and/or activities of lung phagocytes, and the development of CLE, we", + "will be in a position to use this knowledge to test and find methods of altering", + "the activities of lung phagocytes in order to medife or prevent the development", + "of CLE.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.410444, + 0.039945, + 0.020758, + 0.009166 + ], + [ + 0.099152, + 0.057593, + 0.310025, + 0.010432 + ], + [ + 0.134199, + 0.082916, + 0.607905, + 0.011209 + ], + [ + 0.134257, + 0.09548, + 0.623724, + 0.010918 + ], + [ + 0.134865, + 0.107921, + 0.599662, + 0.011238 + ], + [ + 0.13413, + 0.120401, + 0.631252, + 0.011399 + ], + [ + 0.134012, + 0.132177, + 0.661357, + 0.012103 + ], + [ + 0.134508, + 0.14475, + 0.631121, + 0.011866 + ], + [ + 0.133438, + 0.156599, + 0.616851, + 0.012454 + ], + [ + 0.133259, + 0.168909, + 0.616168, + 0.013393 + ], + [ + 0.133872, + 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"phagocytes by stimulating lung phagocytes to make factors which attract monocytes", + "and/or neutrophils into the lung and that cigarette smoking stimulates lung phagocyte", + "to make increased amounts of highly-reactive o, by-products which damage the lung", + "phagocytes themselves and/or neighboring lung tissue. Injury to the phagocytes", + "by o, by-products causes phagocytes to release enzymes which provide addj tional", + "damage to the lung. These findings support our hypethesis.", + "(1.)Individuals who smoke cigarettes have increased numbers of lung phagocytes,", + "pigment-lader macrophages and to a lessor degree neutrophils, which are", + "strategically located at the primary sites(peripheral airways) of the", + "development of CLE(4-13).", + "(2.)Stimulated lung macrophages have been shown under certain conditions to", + "make factors which attract monocytes and neutrophils(14-16).", + "(3. Stimulated phagocytes are fully capable of making and releasing extra-", + "cellularly large quantities ef toxic O2 bv-products and granular enzymes", + "(17-29).", + "(4.)0, by-products from neutrophils can injure neutrophalls(30) and other", + "tissues (31-35). Enzymes from phagocytes can damage lung tissue (36-37).", + "(5.)The biochemical and enzymatic activities of macrophages from the lungs", + "of cigarette smokers appear to be increased(38-40)", + "Our second working hypothesis is that the rat model of CLE caused by chronic in-", + "haltion of CdCl is an appropriate approach for studying CLE which is frequently", + "2", + "seen in individuals who smoke cigarettes. These findings support this observation.", + "(1. Chronic exposure of rats to CdC1, causes CLE which closely resembles", + "morphologically the CLE of humañ cigarette smokers(41)", + "(2.) Chronic expesure of rats to CdC1, increases the numbers of phagocytes in the", + "lung and the locations, numbers, and types of these phagocytes are similar", + "to the findings in human cigarette smokers (41-44),", + "(3.) Chronic exposure of rats to CdC1, appears to increase the biochemical and", + "enzymatic activities of lung phagocytes so that they resemble the activated", + "lung phagocytes of human cigarette smokers (45).", + "(4.)Cigarette smok.e is the major source of .Cd exposure in humans (46).", + "(5.)Cd is present in a dose-severity relationship in the lungs of cigarette", + "smokers with (47).", + "(6.)Workers chronically exposed to CdC1, develop CLE which is similar to CLE", + "found in human cigarette smokers (48=50).", + "(7.)Cd decreases the activities of SOD and catalase, two enzymes found in", + "phagocytes, which serve to detoxify O, and H,0,, respectively (50-52).", + "(8.)Animal models using exposure to cigarêtte smöke are expensive, technically", + "difficult, require administration of cigarette smoke for long durations,", + "and", + "often don't develop the exact changes seen in the lung pathology or", + "lung phagocytes seen in human cigarette smokers (53).", + "When 1) the increased numbers of phagocytes (?5X or more) in the lungs of cigarette", + "smokers, 2) the frequent infections of older cigarette smokers which stimulate the", + "biochemical activities of lung phagocytes(?2X), and 3) the increased biochemical", + "activities of phagocytes even in the healthy cigarette smokers (?2X) are considered,", + "the potential for cigarette smoke induced phagocyte mediated lung injury may be of", + "amplified significance.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.390491, + 0.040731, + 0.021742, + 0.009615 + ], + [ + 0.578452, + 0.045068, + 0.009458, + 0.012759 + ], + [ + 0.646646, + 0.044568, + 0.074652, + 0.015667 + ], + [ + 0.089143, + 0.071319, + 0.36857, + 0.012853 + ], + [ + 0.118984, + 0.089102, + 0.606762, + 0.014754 + ], + [ + 0.265159, + 0.102364, + 0.475237, + 0.0148 + ], + [ + 0.157635, + 0.126572, + 0.568764, + 0.016081 + ], + [ + 0.34188, + 0.141058, + 0.185918, + 0.012148 + ], + [ + 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Research Plan: This section will be divided into sections on experimental", + "design, detailed technical aspects, and anticipated problems.", + "1. Experimental Design: We will perform experiments to provide answers to", + "the following questions.", + "a. Are there differences in the ability of lung phagocytes from human", + "cigarette smokers or nonsmokers to make factors which attract", + "monocytes and/or neutrophils?", + "(1.)We will search(using Boyden chambers) for factors which attract", + "monocytes and neutrophils in the lavages from the lungs of", + "asymptomatic, voung age matched and nonsmoking control", + "subjects.", + "(2.)We will remove phagocytes from the lungs of human smokers and", + "nonsmokers, incubate them alone or with non chemotactic stimulants", + "such as latex particles,collect the supernatants from these", + "mixtures, and test them for chemotactic activity.", + "b. Are there differences in the biochemical activities of lung phagocytes", + "from human cigarette smokers or nonsmokers?", + "(1.)We will measure the O,uptake, ,H2021 *Oh, SOD, and catalase", + "activities of phagocytes from the lüngs of sFokers and nonsmokers.", + "(2.)We will measure malondialdehyde, SOD, and catalase activities in", + "the lavages from the lungs of human smokers and nonsmokers.", + "(3.)We will measure the Cd levels of triply-washed phagocytes from", + "the lungs of smokers and nonsmokers and correlate these levels", + "with the biochemical activities of the lung phagocytes.", + "c. Do alterations in the numbers and biochemical activities of lung", + "phagocytes alter the development of CLE?", + "(1.)We will determine the numbers and biochemical activities of washed", + "phagecytes from the lungs of rats exposed to various concentrations", + "of CdC1. and correlate these findings with the degree of CLE", + "observed morphologically.", + "(2.)We will also measure malondialdehyde,SoD, and catalase activities", + "of lavage fluids from the lungs of CdC1, treated experimental", + "and control rats.", + "(3.)We will measure the Cd levels of the lavage fluids and the washed", + "phagocytes and correlate these findings with the biochemical", + "measurements and the morphologic determinations of CLE.", + "(4.)We will perform manipulations, alone or in combination, to alter", + "the numbers and activities of phagocytes in the lungs of CdC1,", + "treated rats and correlate these findings with changes in the", + "development or severity of CLE.", + "(a.) IImmunization with BCG or Freunds adjuvant (increases the", + "numbers and biochemical activities of phagocytes, 54)", + "(b.)exposure to 100%0, (increases numbers and activities,54).", + "c.)nitrogen mustard or cytoxan (decreeses the numbers,! 55).", + "it.)diethyldithiocarbamate (DDC) treatment (inhibits SOD,56).", + "(e.)aminotriazole (AMT)treatment (inhibits catalase, 57).", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.403219, + 0.049156, + 0.021528, + 0.009302 + ], + [ + 0.587518, + 0.04516, + 0.138031, + 0.014739 + ], + [ + 0.130199, + 0.072735, + 0.099609, + 0.009124 + ], + [ + 0.231581, + 0.091351, + 0.223519, + 0.010602 + ], + [ + 0.276749, + 0.116075, + 0.516964, + 0.012318 + ], + [ + 0.129296, + 0.128562, + 0.676894, + 0.012022 + ], + [ + 0.134896, + 0.140679, + 0.641991, + 0.012903 + ], + [ + 0.129459, + 0.153326, + 0.653604, + 0.011837 + ], + [ + 0.12885, + 0.165373, + 0.629707, + 0.011823 + ], + [ + 0.775571, + 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+ "text": [ + "2c.", + "K once", + "9. continued.", + "2. Detailed Technical Aspects:", + ".Selection of human subjects and recovery of lung phagocytes: Lung", + "phagocytes will be obtained by standard sterile saline lavage using a modified flexible", + "Tiberoptic bronchoscope which can be wedged and sealed in the appropriate pulmonary", + "subsegment thereby elminating contamination by upper airway celle or substances (58).", + "Dr. Hoidal has performed more than 2000 of these procedures without complication.", + "The", + "procedure has been approved by the Committee for Research on Human Volunteers for the", + "University of Colorado. We have chosen to compare young asymptomatic, age matched", + "smoking and nonsmoking individuals because we are interested in the earliest changes", + "occuring in the phapocytes of cigarette smokers and want to avoid confounding variables", + "such as infection, lung dysfunction, or malignancy, which are commonly found in the", + "older, cigarette smoking individuals. A majority of the lavage fluid is retrievable", + "by gentle aspiration and contains the lung phagocytes.", + "b.Care and exposure of rats to CdC1,: Cesarean-derived pathogen", + "controlled male Sprague Dawley(275-325gm)rats will be obtained from a commercial", + "supplier and kept in clean plastic cages fitted with filters and housed in temp-", + "erature controlled animal quarters. Rats will be fed antibiotic free rat chow and", + "given water ad libitum. Groups of rats will be exposed to polydispersed CdC1, (41)", + "aerosol (1x10 M) in saline using a deVilbiss 35A ultrasonic nebulizer. Rats are exposed", + "for 1 hr/day for 0,40r9 days in a specially designed exhaust hood. Control rats are", + "exposed to saline in similar fashion. Two hours, 2,5, or 10 days after the last", + "exposure to CdC1, or saline, the experimental and control rats are weighed, anesthet-", + "ized by intraperitoneal injection of sodium pentobarbital, and exsanguinated by aortic", + "transection. In our pilot studies these condicions produced changes in the lung", + "pathology and inflammatory cells which closely resembled conditions present in", + "human cigarette smokers.", + ".Recovery of phagocytes and preparation of rat lungs for evaluation", + "of CLE: After sacrifice, experimental and control rats will be divided into two groups.", + "In one half of the rats the lungs will be removed, weighed, and lavaged with sterile", + "saline (measured amounts). For some experiments, homogenates will be made of lavaged", + "phagocytes, lungs previously lavaged for phagocytes, and total un-lavaged lungs. These", + "studies will be done to give an indication of the relative contribution of lung", + "phagocyte and non-lung phagocyte components to the products in the lavage fluid.", + "Lungs from the other half of the experimental and control rats will be fixed by constan", + "25cm. pressure inflation with glutaraldehyde for 2 days(59). Following fixation the", + "lungs are cut sagitally, processed for histologic staining at 5u, and stained with", + "Hematoxalin-Phloxin-Safranin.", + "d. Evaluation of inflammation and CLE morphologically: Following fix-", + "ation, sections from the rat lungs will be evaluated in double blind fashion and", + "scored individually for the presence of mural inflammatory cells, peribronchiolar", + "fibrosis, and eptihelial metaplasia. Multiple sections from each lung and each group", + "of rats will be evaluated. The extent of CLE will be measured in standard fashion", + "by determining the mean linear intercepts in 20 randomly selected fields from 4 section", + "from each lung (60).", + "e Isolation and characterization of phagocytes from lung lavages:", + "Phagocytes are isolated from lung lavages by centrifugation at 400xg, resuspended in", + "Hanks' Balanced Salt Solution(HBSS), and differentially counted by hemocytometer", + "Macrophages are also quantitated and characterized using trypan blue exclusion (viabilit", + "esterase, Wright's Giemsa, and acid phosphatase staining. When indicated and necessay,", + "neutrophils and macrophages can be separated by Ficoll-Hypaque centrifucation(61) and", + "macrophage sf rom lymphocytes with a cell density separator (62)", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.400634, + 0.014631, + 0.021603, + 0.009454 + ], + [ + 0.572663, + 0.029375, + 0.010494, + 0.012015 + ], + [ + 0.119973, + 0.039018, + 0.098855, + 0.009941 + ], + [ + 0.261431, + 0.056764, + 0.507225, + 0.010264 + ], + [ + 0.119661, + 0.068951, + 0.634191, + 0.012774 + ], + [ + 0.11867, + 0.081624, + 0.674106, + 0.012926 + ], + [ + 0.118184, + 0.094558, + 0.682418, + 0.012079 + ], + [ + 0.118672, + 0.107016, + 0.650109, + 0.012054 + ], + [ + 0.11915, + 0.119564, + 0.642116, + 0.012028 + ], + [ + 0.119071, + 0.131924, + 0.64199, + 0.012442 + ], + [ + 0.117826, + 0.144089, + 0.636171, + 0.012258 + ], + [ + 0.117774, + 0.156589, + 0.674233, + 0.011982 + ], + [ + 0.119802, + 0.169322, + 0.657438, + 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0.8703, + 0.7828 + ], + "text": [ + "2d.", + "H", + "9. continued", + "E.Measurement of chemotactic activities: We will collect and test", + "supernatants from the lung lavages for their ability to attract monocytes and/or", + "neutrophils in vitro using Boyden chamber technique(53-64). Monocytes and neutrophils", + "will be separated from heparinized dextran sedimented human blood using Ficoll-Hypaque", + "centrifugation as previously described (63-64). After placing the cells in the top", + "compartment of the chamber, we will count the numbers of cells which move through", + "separating Millipore filters (8u for monocytes, 5u for neutrophils) in response to", + "various concentrations of lavage supernatants, HBSS(random locomotion), or known", + "stimuli, such as C5a, from zymosan activated serum, or synthetic chemotactic peptides", + "(65) in the bottom compartment (stimulated locomotion, chemotaxis) The chambers are", + "then incubated for 3 hours at 37°c. After incubation, the filters are removed, rinsed", + "and stained in a holding rack. The filters are then placed upside down on a microscop", + "slide and permanently mounted for counting. The number of phagocytes that traverse the", + "filter in 5HPF are counted. The chemotactic factors from lung macrophages will be", + "characterized with respect to heat stability, molecular weight, and ether extractabilit", + "as described(14-15).", + "g .Preparation of serum, heat-killed bacteria, and PMA: The subsequent", + "studies of lung phagocyte biochemistry will be done with unstimulated or bacteria or", + "PMA stimulated phagocytes. Serum(for preopsonization, 66) is obtained from 5 normal", + "human subjects or 5 rats, allowed to clot, rimmed, recovered by centrifugation, pooled", + "and then frozen at -70°C for not more than one month. Fresh homologous serum will be", + "used in some experiments. Heat-killed bacteria (HKB) are prepared by heating at 70°C", + "for 30 minutes twice washed Staphylococcy : aureus, 502A which has been grown for 17 hrs", + "at 37°c in Penassay broth (67) Suspensions of HKB are sonicated and diluted with HBSS", + "to yield bacteria to macrophage ratios of 100:1 and bacteria to neutrophil ratios of", + "50:1 ( optimal ratios). MA(12-0-tetradeconyl phorbol-13-acetate, MW616) is dissolved it", + "dimethyl sulfoxide(De(so) at a stock concentration of 2mg/ml and stored in the dark at", + ".°c for two weeks cr until use. Jus: before usé, PMA is diluted with HBSS and used at", + "a concentration of Jug/ml(67-69).", + "h.Measurement of oxygen consumption:0, uptake is assayed on a Yellow", + "Springs biologic 0, electrode attached to a Beckman recorder (67-69). Mixing vials are", + "maintained at 37°C by a circulating water bath and stirred with a magnetically driven", + "stirring bar. Rates of o, uptake are calculated from the maximum slope over a 10 min.", + "6", + "period from a 3ml vial containing 10x10 phagocytgs alone , with preopsonized HKB,", + "or", + "PMA. Data are expressed as 010,/consumed/hr/5x10 phagocytes.", + "1.Measurement of superoxide anion release:0, release is determined b", + "measuring", + "SOD inhibitable horse heart ferricytochrome c réduction spectrophoto-", + "netrically at 550nn(68-70). Reaction mixtures (1m1) contain 5x10 phagocytes in HBSS.", + "In some samples, HKB or PMA are added. One of a pair of mixtures is incubated for 20", + "min. at 37 C;the other is kept on ice and used as a blank. Specificity of cytochrome", + "C reduction is determined by using identical mixtures which also contain 50ug/ml SOD.", + "After incubation, the mixtures are rapidly cooled to 4°C and centrifuged at 800xg for", + "20 min. Supernatants are assayed spectrophotometrically and the results are copverted", + "-I", + "to nanomoles of SOD inhibitable cytochrome C reduced/20min. (E -2.1 x 10 m em \").", + "550nm", + "j.Measurement of hydrogen peroxide production:H,0 is measured using", + "the scopoletin assay(71).Briefly the 460nm emission from reduced scopoletin excited by", + "light is extinquished when scopoletin is oxidized by in the presence of horse-", + "radish peroxidase(MPO). The loss of flourescence is proportionel to the concentration", + "cf H.o. The reaction mixtures contain 5x10 phagocytes in HBSS, HKD or PMA solutions", + "202", + "at 37°C and 10mN scopoletin to which 22mM HPO is added. 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We will use the standard gas chromatographic analysis of ethylene produced", + "by", + "phagocytes with and without inhibitors (19-21). We will again study phagocytes", + "alone, following stimulation with HKB or PMA, with and without inhibitors such as", + "SOD, catalase, ethancl, tryptophan, benzoate, thiourea, DABCO, azide. and histidine.", + "In addition we have been working the past year and one half on a new assay for .OH", + "radical which we feel will be more specific than conventional assays. The work on this", + "approach will be completed in all likelihood before the start of this grant.", + "1.Measurement of superoxide dismutase:SOD is determined by measuring", + "the rate of inhibition of the spontaneous oxidation of pyrogallo] at 41 5nm in Tris", + "buffer,pH8.3(72) Briefly, samples from homogenates of phagocytes or concentrated", + "lavages are added to a stock solution of pyrogallol in dilute HCI. The resultant", + "mixture is then added to a 3cc. of the Tris buffer and the rate of oxidation of pyro-", + "gallol is recorded on a Beckman recorder- attached to a spectrcphotometer. The degree", + "of inhibition of the rate of oxidation is compared to a purified standard.", + "m.Measurement of catalase:Catalase is measured using a biologic O2", + "probe attached to a recorder to determine the 0, produced by the catalase sample", + "upon addition of Sul of H.O. (73). The linear increase in 0, concentration is recorded", + "for 2 min. A standard curve is constructed using purified commercial bovine liver", + "catalase. The results are expressed as units/mg protein/min.", + "n.Measurement of malondialdehyde:MI is a by-product of the reaction", + "of free radicals with lipids and is measured by a standard method(74). Reaction mix-", + "tures are incubated and then terminated by the addition of 0.5%(w/v) trichloroacetic", + "acid per ml. of incubation mixture. Then, 1 ml of 0.5% 2-thiobarbituric acid is added", + "per ml. of the incubation mixture and the tube is heated at 60 for 90 min. After", + "cooling, 1 ml of 70. trichloracetic acid is added to each tube. Then, 3 ml chloroform", + "is added and the tubes are shaken to remove dispersed lipid. The samples are then", + "centrifuged a.d read spectrophotometrically at 532nm.", + "Measurement of cadmium:Cd is measured using the established", + "technique(75). Tissues and samples for measurement of Cd must be handled and prepared", + "for Cd analysis with care to avoid contamination. Samples are dried at 100°C for 24hr", + "and ashed with the temperature carefully controlled at 450°C for 48 hr. The ash is", + "then dissolved in 5ml of 6N nitric acid and assayed in duplicate for cadmium by", + "atomic absorbtion spectroscopy, using the Perkin Elmer 403 with an attached deuterium", + "arc for background collection. A number of other ions such as zinc, sodium, potassium,", + "and calcium can also be measured by this technique aad used for control purposes.", + "p.Analyzation of data and statistics:Granted that the initial studies", + "will involve extensive data collection, we have already performed enough experiments", + "to focus our investigation and allow us to persue times and concentrations of CdC1,", + "which produce changes typical of CLE in cigarette We will perform the4", + "studies with large groups of rats and undertake enough experiments so that statistical", + "analysis can be applied appropriately to determine differences between experimental", + "and control situations (76).", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.600018, + 0.027582, + 0.130529, + 0.016257 + ], + [ + 0.369431, + 0.078324, + 0.021964, + 0.009254 + ], + [ + 0.110057, + 0.088819, + 0.101548, + 0.009866 + ], + [ + 0.206123, + 0.113809, + 0.547011, + 0.011834 + 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An attempt has been made to discover potential", + "problems in order to find methods by which they", + "might be minimized or accounted for in interpret-", + "ation.", + "3. Spedific phagocyte causing CLE: Macrophages and/or neutrophils", + "could be responsible for the CLE found in cigarette smokers. In the present studies", + "we have elected to initially not try to distinquish between the roles played by each", + "cell individually until we ':ave clearly documented that phagocytes play a role in CLE.", + "Techniques are available for separating macrophages from neutrophils so that we can", + "undertake this clarification of our findings at the appropriate time. The evidence", + "available suggests that macrophages and/or neutrophils could be involved in the de-", + "velopment of CLE. The normal lung contains macrophages and few if any neutrophils.", + "Lavages of normal nonsmoking individuals yield on the average 20 million macrophages", + "with less than 1%: neutrophils. Lavages of young, asymptomatic smokers yield 100", + "million macrophages with 5-8% neutrophils. In our pilot studies we have found that", + "rats exposed to large concentrations of CdC12 acutely develop lung injury but more of", + "a panlobular type. In contrast rats exposed to smaller concentrations of CdC1, in a", + "chronic fashion develop CIE and lavages contain markedly increased numbers of macro-", + "phages(5-9x) and approxinately 5% neutrophils. While the increased numbers of macro-", + "phages relative to neutrophils clearly favors this cell type as a prime factor, we", + "know that the biochemical activities of stimulated neutrophils is 3-6X the metabolic", + "activities of macrophages. We will keep the various numbers and biochemical activities", + "of these two lung phagocytes in mind and not attribute lung injury to one or the other", + "of them until we have firm evidence to support their involvement.", + "b. Infection:The presence of lung infection in humans or animals pro-", + "foundly affects the nature of airway inflammation, the function of lung phagocytes, and", + "the development of CLF. To minimize this problem we will use rats. Our previous", + "work has shown that there are similar patterns in the metabolic activities of macro-", + "phages from the lungs of humans and rats and that there is a low incidence of infection", + "in rats. We will take every precaution to keep animals free of infection. However,", + "we will still continue to culture lavage materials from the lungs of experimental and", + "control subject to monitor this problem.", + "c. Non-representative nature of the lavage samples: Another concern is", + "that the phagocyte content of the lavage returns do not accurately reflect the phago-", + "cytes present in the total lung. This problem is amplified because the cells in the", + "lavages come from all areas of the lung and not just areas of inflammation or injury.", + "Fortunately, CLE is a diffuse process. Attempts to determine the validity of this", + "concern by obtaining cells from minced lungs and comparing the numbers and types and", + "functions with lavage results have not revealed any remarkable differences. However,", + "the approach is complicated by the contamination of lung minces with mar.; interstitial", + "cells. Another reassurance that the lavage may accurately reflect lung conditions is", + "our previous work which shows that relatively only a few phagocytes remain in the lung", + "following lavage and the increases numbers of phagocytes are primarily in the", + "bronchioles where we know that they are effectively recovered by lavage.", + "d. Lack of specificity of some of the reagents: Some of the manipul-", + "ations suggested to alter the numbers and/or biochemical activities of phagocytes in", + "the lung are not specific for this feature alone we will run controls with the", + "agents alone and consider this in our interpretation of the results. Likewise some", + "of the reagents used to scavenge activated o, by-products are not entirely specific", + "and interpretation of their specificity must be undertaken with considerable caution.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.621772, + 0.0, + 0.138917, + 0.004075 + ], + [ + 0.382506, + 0.035629, + 0.015686, + 0.01034 + ], + [ + 0.60502, + 0.030943, + 0.114602, + 0.015185 + ], + [ + 0.11021, + 0.045356, + 0.100607, + 0.009223 + ], + [ + 0.149125, + 0.07066, + 0.270923, + 0.010834 + ], + [ + 0.186625, + 0.095311, + 0.593342, + 0.012057 + ], + [ + 0.109427, + 0.107652, + 0.615112, + 0.012127 + ], + [ + 0.110002, + 0.120212, + 0.645313, + 0.011906 + ], + [ + 0.109228, + 0.132626, + 0.67783, + 0.011839 + ], + [ + 0.109025, + 0.144439, + 0.670455, + 0.012131 + ], + [ + 0.109504, + 0.157138, + 0.622514, + 0.01145 + ], + [ + 0.108016, + 0.169508, + 0.647113, + 0.011754 + ], + [ + 0.110954, + 0.181234, + 0.656324, + 0.012661 + 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Importance of the Proposed Work:", + "Centrilobular emphysema (CLE) resulting from cigarette smoking is an important", + "and common clinical problem. The incidence, morbidity, and mortality of amokers.", + "is very impressive. In the United States alone, approximately 50% of the population", + "smokes cigarettes and mere than 25,000 people die of emphysema each year at an estimated", + "cost of greater than 1.5 billion dollars (77). Since campaigns to encourage individuals", + "to quit smoking cigarettes have beea unsuccessful(1) better understanding of the", + "mechanisms linking cigarette smoking to emphysema need to be determined so that more", + "effective methods of interrupting lung injury can be found. Additional information oi", + "use may also come from the proposed studies. First, we may be able to determine if", + "chere is a mechanism underlying the ability of certain individuals to smoke cigarettes", + "and yet avoid any emphysema. If we can discover this information we will be in a", + "position to test individuals and determine if they are unusually susceptible to the", + "toxic effects of rigarette smoke. Second, we may be able to apply the information", + "to improve understanding of the toxic effects of cigarette smoke on a number of other", + "organs other than the lung such as the heart and the vessels. Third, since phagocytes", + "are involved in the pathogenesis of a number of lung diseases which are not related to", + "cigarette smoking, the proposed studies may provide information which may be basic", + "to elucidating the role of phagocytes in a variety of lung injuries.", + "c. Previous Work on this or Related Projects by the Applicants:", + "We hove performed many investigations during the past seven years to determine", + "the", + "activities of lung phagocytes and these are summarized in the biographies of the", + "applicants. We have also been working on this project for the last year. The most", + "relevant work will be summarized below.", + "(1.) Published studies: We have documented", + "-", + "(a.) that Human alveolar macrophages consume 0,, make 0, , and OU when", + "stimulated by bacteria or phorbol myristate acetate: AM increase thesé activities.", + "(b.)that the metabolic. activities of lung macrophages from rats, rabbits,", + "and human subjects are similar.", + "(c. ) that lung macrophages from cigarette smokers have decreased adherence", + "and altered surface morphology.", + "(2.) Unpublished preliminary studies: We have found", + "(a.) that factors which attract neutrophils in vitro can be isolated from", + "the lung lavages of animals exposed to 100% o, and that lung macrophages in culture in", + "response to 100: 0, make factors which attract neutrophils in vitro.", + "(b.) that malondialdehyde can be isolated from the lavages of the Jungs", + "of", + "animals exposed to 100% o, and in concentrations which exceed those found in control", + "animals which have been exposed to room air.", + "(c.) that there are increased numbers of macrophages and neutrophils in", + "the", + "lavages of the lungs of young, asymptematic cigarette smokers compared to non-", + "smoking age~matched control subjects.", + "(d.) that the 0,- production of macrophages from the young cigarette", + "smokers is increased compared to macrophages from nonsmoking controls. This is in", + "spite of the fact that the o, uptake of the smoker and nonsmoker macrophages are equal.", + "The basis of this finding could be related to the decreased SOD activities we have", + "found in the macrophaçes from the cigarette smokers. The differences in the biochemical", + "activities of smoker macrophages can not be explained on the basis of cell size and/or", + "protein differences in the smoker and nonsmoker macrophages. These findings support", + "our assumption that Cd frem cigarette smoke may have altered the SOD content oi the", + "lung macrophages and that this is reflected in increased production of C2-.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.404857, + 0.048024, + 0.015056, + 0.009565 + ], + [ + 0.582837, + 0.037808, + 0.121748, + 0.016838 + ], + [ + 0.125622, + 0.056208, + 0.096838, + 0.008908 + ], + [ + 0.233814, + 0.074832, + 0.545087, + 0.013412 + ], + [ + 0.124661, + 0.087285, + 0.64132, + 0.012141 + ], + [ + 0.124889, + 0.099793, + 0.640882, + 0.016445 + ], + [ + 0.125333, + 0.111543, + 0.616958, + 0.012999 + ], + [ + 0.124836, + 0.12407, + 0.55477, + 0.012464 + ], + [ + 0.163056, + 0.148636, + 0.445726, + 0.011947 + ], + [ + 0.202334, + 0.173765, + 0.579148, + 0.011451 + ], + [ + 0.124423, + 0.185367, + 0.008523, + 0.009324 + ], + [ + 0.138879, + 0.185906, + 0.627051, + 0.012277 + ], + [ + 0.124988, + 0.197859, + 0.658476, + 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Specifically rats administered CdC12 have", + "increased numbers of macrophages and the 0,- production of these macrophages is", + "increased over levels produced by macrophages from saline exposed rats.", + "D. Results of this or Similar Project Obtained by Others:", + "The primary supporting evidence for this work has been provided in section", + "8", + "of the grant application. To our knowledge we are the only individuals pursuing", + "the role of O2 by-products in the production of CLE using a comprehensive approach o", + "comparing humän Sand rats exposed to CdC1,- There is however wide and increasing", + "interest regarding the role of phagocytes in lung injury and the nature and mechanisr", + "responsible for phagoryte locomotion, biochemical and enzymatic function and tissue", + "injury. We are also aware that the measurement of 0, by-products is a sophisticated", + "undertaking. We will be aware cf any developments that occur in these areas and", + "modify our approaches appropriately during the course of the investigations.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.396951, + 0.034965, + 0.014868, + 0.009264 + ], + [ + 0.123283, + 0.054088, + 0.080892, + 0.009553 + ], + [ + 0.124891, + 0.078336, + 0.67228, + 0.014686 + ], + [ + 0.124554, + 0.092585, + 0.013037, + 0.008693 + ], + [ + 0.146819, + 0.090843, + 0.644236, + 0.015303 + ], + [ + 0.147507, + 0.103547, + 0.498312, + 0.013502 + ], + [ + 0.124645, + 0.115464, + 0.623242, + 0.01477 + ], + [ + 0.146827, + 0.128169, + 0.641309, + 0.01476 + ], + [ + 0.145892, + 0.141288, + 0.248701, + 0.011546 + ], + [ + 0.122717, + 0.153866, + 0.014464, + 0.009158 + ], + [ + 0.14551, + 0.152613, + 0.621625, + 0.014627 + ], + [ + 0.145979, + 0.166226, + 0.10185, + 0.010521 + ], + [ + 0.144994, + 0.177295, + 0.637623, + 0.014565 + ], + [ + 0.146002, + 0.19055, + 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"J.", + "ir Spuc\" and available (when elsewhore tion item 2 indicates, state location;-", + "For this project we will have access to the facilities of the Webb-Waring Lung", + "Institute. These include a space assigned to us of approximately 3000 sq. ft.", + "The Webb-Waring is equipped with sophisticated animal quarters and ecuipment for", + "transmission electron microscopy There are also facilities for culture. The", + "equipment available includes scintillation counters, centrifuges, microscopes,", + "aerosol equipment, spectrophotometer; freezers, oxygen monitor, and sterilization", + "equipmert. The University of Colorado is an excellent training center for pulmonary", + "physicians so many patients are available for study by bronchoscopy. In addition", + "there are a large number of investigators interested in macrophage function and", + "structure, lung pathology, and cellular immunology in the Webb-Waring Lung Institute", + "and the surrounding University of Colorado Medical Center and National Jewish", + "Hospitals.", + "11. Additional facilities required:", + "None", + "12. Biographical sketches of investigator(s) and other professional personnel (append):", + "13. Publications: (five most recent and pertinent of investigator(s); append list. and provido reprints if available).", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.055106, + 0.037774, + 0.119879, + 0.010884 + ], + [ + 0.081514, + 0.05074, + 0.267889, + 0.010262 + ], + [ + 0.115629, + 0.063025, + 0.225667, + 0.010725 + ], + [ + 0.128059, + 0.073556, + 0.147424, + 0.01063 + ], + [ + 0.087406, + 0.096626, + 0.347223, + 0.011295 + ], + [ + 0.113601, + 0.191691, + 0.050483, + 0.008942 + ], + [ + 0.086786, + 0.209613, + 0.236155, + 0.009455 + ], + [ + 0.103701, + 0.222008, + 0.118353, + 0.01125 + ], + [ + 0.08717, + 0.246214, + 0.360965, + 0.011053 + ], + [ + 0.103638, + 0.258907, + 0.11836, + 0.011059 + ], + [ + 0.462765, + 0.306191, + 0.084253, + 0.008986 + ], + [ + 0.077679, + 0.323652, + 0.241873, + 0.011921 + ], + [ + 0.086365, + 0.340969, + 0.058018, + 0.009241 + ], + [ + 0.087066, + 0.353037, + 0.150804, + 0.009378 + ], + [ + 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Leavenworgh,Director_ OGC", + "4200 Eant Ninth Avenue", + "Denver, Colorado 80262", + "16. Other sources of financial support.", + "List financial support from all sources, including own institution, for this and related research projects", + "Inclusive", + "All of our present", + "support for this and", + "related projects is", + "local (Minnesota)money", + "which will not be", + "available when we move", + "to the Webb-Waring Lung", + "Institute in Denver in", + "July, 1979.", + "PENDING OR PLANNED", + "Source", + "Title of Project", + "(give grant numbers)", + "Phagocyte Mediated Luns", + "American Heart Assoc.", + "Injury in 0,-Toxicity", + "Mechanisms of 0,", + "National Institutes of", + "Induced Lung Injury", + "Health", + "Typed Name", + "Signature Date", + "Tolephone", + "3.", + "il E0316149", + "CURRENTLY ACTIVE", + "Source", + "Title of Project", + "Dates", + "(give grant numbers)", + "Amount", + "Inclusive", + "Amount", + "Dates", + "July 79-81.", + "(20,000/yr", + "July 79-81.", + "50,000/yr", + "I", + "Principol investigators", + "John R. Hoidal", + "John E. 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Cowee", + "Title Signate/ Chancellor Kath Data 12/19/78", + "7682", + "Tolephone", + "Areo Code", + "Number", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.404111, + 0.028229, + 0.009865, + 0.006734 + ], + [ + 0.565302, + 0.041726, + 0.11765, + 0.015087 + ], + [ + 0.09418, + 0.062042, + 0.203325, + 0.010269 + ], + [ + 0.129007, + 0.074404, + 0.550596, + 0.010611 + ], + [ + 0.353631, + 0.100444, + 0.111775, + 0.008645 + ], + [ + 0.383546, + 0.117711, + 0.03609, + 0.008326 + ], + [ + 0.625374, + 0.117748, + 0.045085, + 0.008299 + ], + [ + 0.164571, + 0.127445, + 0.075559, + 0.010351 + ], + [ + 0.344325, + 0.128262, + 0.110999, + 0.009945 + ], + [ + 0.52671, + 0.128676, + 0.041372, + 0.007579 + ], + [ + 0.632022, + 0.127967, + 0.030934, + 0.008596 + ], + [ + 0.114124, + 0.151273, + 0.144207, + 0.010791 + ], + [ + 0.114576, + 0.163066, + 0.159706, + 0.011865 + ], + [ + 0.115001, + 0.176065, + 0.151716, + 0.010919 + ], + [ + 0.11496, + 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Other sources of financia: suppon", + "List financiali support from all sources, including own institution, for this and related research projects.", + "CURRENTLY ACTIVE", + "Source", + "inclusive", + "Tutle of Project", + "(give grant numbers)", + "Amount", + "Dates", + "All of our present", + "support for this and", + "related projects is", + "local (Minnesota) money", + "which will not be", + "available when we move", + "to the Webb-Waring Lung", + "Institute in Denver in", + "July, 1979.", + "PENDING OR PLANNED", + "Source", + "Inclusive", + "Title of Project", + "(give grant numbers)", + "Amount", + "Dates", + "Phagocyte Mediated Luns", + "20,000/yr", + "July 79-81.", + "American Heart Assoc.", + "Injury in 0,-Toxicity", + "Mechanisms of 02", + "National Institutes of", + "Induced Lung Injury", + "50,000/yr", + "July 79-81.", + "Health", + "is undersicod that the investigator and institutional", + "Principal investigator s", + "icers in opplying ior o grant have read and accept", + "John E. 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Biographical Sketches.", + "Curriculum Vitae", + "Repine, John, E., M.D.", + "Assistant Director, Webb-Waring Lung Institute", + "Associate Professor of Medicine", + "University of Colorado Medical Center", + "U.S. Citizen, born Rock Island, Illinois,December 26,1944 (age 33)", + "Education and Professional Experience", + "Degree", + "Year", + "University of Wisconsin, Madison, Wisconsin", + "B.S.", + "1966", + "University of Minnesota, Minneapolis, Minnesota", + "M.D.", + "1971", + "Internship, Internal Medicine Residency, and", + "Pulmonary Medicine Fellowship-University of", + "Minnesota Health Sciences Center", + "1971-75", + "Instructor, Dept. of Medicine, Univ. of Minnesota", + "1974-75", + "Asst. Prof. ,Dept. of Medicine, Univ. of Minnesota", + "1975-78", + "Assoc. Prof., Dept. of Medicine, Univ. of Minnesota", + "1978-79", + "Assec. Prof., Dept. of Medicine, Univ. of Colorado", + "Asst. Dir. Webb-Waring Lung Institute", + "1979-", + "Honors", + "Evans Scholar", + "SAMA Scientific Exhibit Award", + "Young Pulmonary Investigator Award(NIH)", + "Mead-Johnson Grand award for Research by a Resident-SAMA-UTMB-1971", + "Minnesota Heart Fellowship", + "Basil O'Connor Starter Research Award - March of Dimes", + "Graduate Research Award(NIH)", + "Established Investigator Award (American Heart Associacion,1976-1981).", + "Selected Bibliography-Published Manuscripts and manuscripts accepted for", + "publication", + "Repine JE, White JG, Clawson CC and Holmes BM: The influence of phorbol myristate", + "acetate on oxygen consumption by polymorphonuclear leukocytes.J Lab Clin Med83:911,1974", + "Repine JE, White JG, Clawson CC and Holmes BM: Effects of phorbol myristate acetate on", + "the metabolism and ultrastructure of neutrophils in chronic granulomatous disease.", + "J Clin Invest 54:83,1974.", + "Repine JE, White JG, Clawson CC and Holmes BM: The influence of phorbol myristate", + "acetate on the metabolism of neutrophils from carriers of sex-linked chronic", + "granulomatous disease. J Lab Clin Med 85:82,1975.", + "Repine JE, Clawson cc, White JG and Holmes BM: Spectrum of function of neutrophils from", + "carriers of sex-linked chronic granulomatous disease. J Pediatrics 87:813,1975.", + "Repine JE, Clawson cc, and Brunning RD: Primary leukocyte alkaline phosphatase", + "deficiency in an adult with repeated infections. Brit J Hemat 34:87,1976.", + "Repine JE, Clawson cc, Burchell HB, and White JG: Reversible neutrophil bactericidal", + "defect in bacterial endocarditis. J Lab Clin Med 88:780,1976.", + "Repine JE, Clawson cc. and Brunning RD: Abnormal pat tern of bacterial killing by", + "neutrophils deficient in granules, alkaline phosphatase, and myeloperoxidase. J Lab", + "Clin Med 88:788,1976.", + "Repine JE, Clawson cc, and Friend PS: Influence of a deficiency of the second component", + "of complement on the bactericidal activity of neutrophils in vitro. J Clin Invest 59:", + "802,1977.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.38776, + 0.061291, + 0.013959, + 0.009654 + ], + [ + 0.534912, + 0.059682, + 0.009884, + 0.013242 + ], + [ + 0.108572, + 0.093662, + 0.654083, + 0.01939 + ], + [ + 0.117698, + 0.107061, + 0.645896, + 0.018299 + ], + [ + 0.115515, + 0.122295, + 0.126453, + 0.011293 + ], + [ + 0.108734, + 0.131876, + 0.676652, + 0.017989 + ], + [ + 0.116269, + 0.144184, + 0.661832, + 0.018597 + ], + [ + 0.115888, + 0.158899, + 0.1929, + 0.012947 + ], + [ + 0.107981, + 0.168865, + 0.630714, + 0.018192 + ], + [ + 0.114317, + 0.180868, + 0.639729, + 0.018054 + ], + [ + 0.115404, + 0.19654, + 0.131614, + 0.011597 + ], + [ + 0.107364, + 0.205231, + 0.670852, + 0.019346 + ], + [ + 0.116125, + 0.219146, + 0.51038, + 0.015894 + ], + [ + 0.107605, + 0.230434, + 0.655231, + 0.018632 + ], + [ + 0.114621, + 0.243637, + 0.497027, + 0.016797 + ], + [ + 0.107418, + 0.254611, + 0.669939, + 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Clawson CC: Quantitative measurement of the bactericidal capability of", + "neutrophils from patients and carriers of chronic granulomatous disease. J Lab Clin", + "Med 90:522,1977.", + "Beall GD, Repine JE, Hoidal JR, and Rasp FL: Chemiluminescence of human alveolar macro-", + "phages: Stimulation with heat-killed bacteria or phorbol myristate acetate. Infection", + "and Immunity 17:117,1977.", + "Repine JE, Rao G. Beall GD and White JC: Inhibition of human neutrophil oxidative", + "metabolism and degranulation in vitro by nitroblue tetrazolium and vitamin E. Am J", + "Path 90:659,1978.", + "Repine JE, Clawson cc, Rasp FL, Sarosi, GA, and Hoidal JR: Defective neut rophil chemo-", + "taxis in human blastomycosis: Evidence for a serum inhibitor. ARRD", + "Repine JE and Clawson CC: Influence of surface proteins and separation techniques on", + "neutrophil unstimulated and stimulated locomotion in vitro. JRES", + "Rasp FL, Clawson cc, Hoidal JR, and Repine JE: Adherence of human alveolar macrophages", + "and polymorphonuclear leukocytes to nylon fiber in vitro: Quantitation and scanning", + "electron microscope comparison. JRES", + "Rasp FL, Clawson CC, and Repine JE: Comparison of the adherence and morphology of", + "alveolar macrophages from smokers and nonsmokers. ARRD", + "Repine JE, Hoidal JR, and White JC: Effect of temperature on the chemiluminescence of", + "human neutrophils in vitro. In The Biology of Oxygen Radicals, w.s. Caughy, ed.", + "Academic Press, Inc, New York, NY.", + "Abstracts not subsequentally published in full (Selected list)", + "Rasp F1, Repine JE, Hoidal JR, and Sarosi GA: Decreased adherence in vitro of poly-", + "morphonuclear leukocytes (PMN) from patients with invasive fungal infections (IFI)", + "ARRD 115:199,1977.", + "Beall GD, Repine JE, Hoidal JR, and Rasp FL: Generation of hydroxyl radical( OH) by", + "humen alveolar macrophages(AM). ARRD 117:269,1978", + "Hof DG, Repine JE, Petersen PK, Hoidal JR, and Quie PG: Opsonic requirements and kinetics", + "of phagocytosis by alveolar macrophages (AM) ARRD117:275,1978.", + "Fox RB, Eaton JW, Repine JE. and Brown DB: Ontogeny of cytoplasmic superoxide dis-", + "mutase (SOD) activity in fetal and neonatal lung tissues. Amer Rev Resp Dis, April 1979.", + "Fox RB, Hoidal JR, Takiff HE, and Repine JE: Pretreatment with Freund's adjuvant", + "increases the numbers of alveolar macrophages and protects against pulmonary oxygen", + "toxicity. Amer Rev Resp Dis, April , 1979.", + "Repine JE and Friend PS: Function of polymorphonuclear leukocytes(PMN) from a patient", + "with an inherited absence of the fourth component of complement (c4). ARRD April, 1979.", + "Rasp FL and Repine JE: Bacteria, fungi, and chemicals increase adherence of poly-", + "morphonuclear leukocytes(PMN causing chemiluminescence(CL) and release of lysozyme(LY)", + "Amer Rev Resp Dis April, 1979.", + "Hoidal JR and Repine JE: A congenital defect in human alveolar macrophage(AM function:", + "Absence of increased (0,) uptake, superoxide anion(o,\") production, and glucose", + "oxidation by AM from a patient with chronic granulomätous disease(CGD) Amer Rev", + "Resp Dis April, 1979.", + "Hoidal JR, Fox RB, Takiff HE, and Repine JE: Alveolar macrophages(AM) from young", + "asymptomatic cigaretta smokers use equal amounts of oxygen(02) and glucose (1-14c)", + "but smoker AM make more superoxide anion(0,- Amer. Rev Resp Dis April, 1979.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.39338, + 0.019671, + 0.013226, + 0.009151 + ], + [ + 0.313701, + 0.053633, + 0.122847, + 0.009154 + ], + [ + 0.110749, + 0.07814, + 0.163584, + 0.010417 + ], + [ + 0.110474, + 0.090614, + 0.241425, + 0.009567 + ], + [ + 0.109947, + 0.113373, + 0.491509, + 0.013425 + ], + [ + 0.109576, + 0.139978, + 0.287293, + 0.011218 + ], + [ + 0.54964, + 0.13946, + 0.044669, + 0.010346 + ], + [ + 0.640633, + 0.138433, + 0.032042, + 0.009628 + ], + [ + 0.108921, + 0.165196, + 0.327771, + 0.010976 + ], + [ + 0.555779, + 0.164508, + 0.029438, + 0.009006 + ], + [ + 0.640993, + 0.16345, + 0.031508, + 0.009461 + ], + [ + 0.108309, + 0.177116, + 0.3679, + 0.011635 + ], + [ + 0.554407, + 0.17696, + 0.02957, + 0.009097 + ], + [ + 0.640781, + 0.176145, + 0.031226, + 0.009503 + ], + [ + 0.109722, + 0.189647, + 0.381543, + 0.01125 + ], + [ + 0.632838, + 0.188454, + 0.05601, + 0.009421 + 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M.D.", + "Assistant Professor of Medicine", + "U. s. Citizen, born akland,California, January 22, 1944(age34).", + "Education and Professional Experience", + "Degree", + "Year", + "Jamestown College, Jamestown, North Dakota", + "B.S.", + "1965", + "University of Minnesota, Minneapolis, Minnesota", + "M.D.", + "1969", + "Internship, Univeristy of Colorado Medical Center", + "1969-70", + "Resident, Internal Medicine, University of Minnesota", + "1970-72", + "Chief Resident, Internal Medicine, University of", + "Minnesota", + "1972", + "Pulmonary Fellow, University of Minnesota", + "1973-75", + "Instructor, University of Minnesota", + "1974-75", + "Asst. Prof., University of Minnesota", + "1975", + "Honors", + "Summa cum laude at Jamestown College", + "Alpha Omega Alpha at University of Minnesota", + "Board Certified Internal Medicine and Pulmonary", + "Selected Bibliography- Published Manuscripts and manuscripts accepted for", + "Publication", + "Hoidal JR, Repine JE, Beall GD, Rasp FL, and White JG: The effect of phorbol myristate", + "acetate on the metabolism and ultrastructure of human :liveolar macrophages. Amer.", + "J.", + "Path 91:469,1978", + "Hoidal JR, Beall GD, Rasp FL, Holmes B, White JG, and Repine JE: Comparison of the", + "metabolism of alveolar macrophages from humans, rats, and rabbits: Response to heat-", + "killed bacteria or phorbol myristate acetate. J Lab Clin Med 92:787,1978.", + "Ackerman SK, Friend PS, Hoidal JR, and Douglas SD: Production of C2 by human alveolar", + "macrophages. Immunol 35:369,1978.", + "Repine JE, Rasp FL, Clawson cc. Sarosi GA, and Hoidal JR: Defective neutrophil chemo-", + "taxis is patients with bastomycosis: Evidence for a serum inhibitor. Amer Rev", + "Resp Dis 118:325,1978.", + "Beall GD, Repine JE, Hoidal JR, and Rasp FL: Chemiluminescence of human alveolar", + "macrophages: Stimulation with heat-killed bacteria or phorbol myristate acetate", + "Infect and Immunity 17:117,1977.", + "Hoidal JR, White JG and Repine JE: Impairment of human alveolar macrophage oxygen", + "consumption and superoxide anion production by local anesthetics used during", + "bronchoscopy. Chest", + "Repine JE, Davies SD, and Hoidal JR: Effect of C2 on the bactericidal activity and", + "chemiluminescence responses of human neutrophils in vitro. Chest", + "Repine JE, Hoidal JR, and White JG: Effect of temperature on the chemiluminescence of", + "human neutrophils in vitro, In The Biology of Oxygen Radicals, W.S.Caughy,ed", + "Academic Press, Inc, New York, NY.", + "Rasp FL, Clawson cc, Hoidal, JR and Repine JE: Adherence of human alveolar macrophages", + "and polymorphonuclear leukocytes from smokers and non-smokers in vitro. JRES", + "Hoidal JR, White JG, and Repine JE: Influence of cationic local anesthetics on the", + "metabolism and ultratructure of human alveolar macrophages. J Lab Clin Med", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + }, + { + "bbox": [ + [ + 0.416639, + 0.013414, + 0.014554, + 0.009329 + ], + [ + 0.126116, + 0.05383, + 0.469413, + 0.011618 + ], + [ + 0.12743, + 0.078255, + 0.659457, + 0.012214 + ], + [ + 0.13469, + 0.090651, + 0.629837, + 0.012289 + ], + [ + 0.134876, + 0.103534, + 0.303903, + 0.011076 + ], + [ + 0.126887, + 0.115696, + 0.660108, + 0.012146 + ], + [ + 0.134692, + 0.127992, + 0.483059, + 0.011696 + ], + [ + 0.126227, + 0.140649, + 0.628781, + 0.011475 + ], + [ + 0.134187, + 0.152948, + 0.312953, + 0.011163 + ], + [ + 0.126381, + 0.165133, + 0.644597, + 0.011457 + ], + [ + 0.133037, + 0.177474, + 0.622298, + 0.011161 + ], + [ + 0.13396, + 0.189739, + 0.167869, + 0.011151 + ], + [ + 0.127082, + 0.201663, + 0.65038, + 0.011821 + ], + [ + 0.134054, + 0.214406, + 0.652637, + 0.011559 + ], + [ + 0.134594, + 0.227136, + 0.60538, + 0.011226 + ], + [ + 0.133721, + 0.239142, + 0.185371, + 0.011141 + ], + [ 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Amer Rev Resp Dis 117:275,1978.", + "Beall GD, Repine JE, Hoidal JR, Rasp FL, and White JG: Generation of hydroxyl radical", + "by human alveolar macrophages. Amer Rev Resp Dis 117:269,1977.", + "LeMarbe P, Hoidal JR, Besella R, and Rinehart J: Human pulmonary macrophage tumor", + "cell cytotoxicity. Clin Res 26:669,1978.", + "Rasp FL, Repine JE, Hoidal JR, and Sarosi GA: Decreased adherence in vitro of poly-", + "morphonuclear leukocytes from patients with invasive fungal infections. Amer Rev", + "Resp Dis 115:258,1977.", + "Smith CM, Tukey DP, Mundshenk D, Repine JE, and Hoidal JR: Alveolar macre phages (AM)", + "deformability: Measurement by positive pressure nucleopore filtration: Alteration by", + "pharmacologic agents and application to AM from human cigarette smokers. Amer", + "Rev Resp Dis April 1979.", + "Davies SD, Hoidal JR, and Repine JE: Chemiluminescence(CL by human polymorphonuclear", + "leukocytes (PMN) and monocytes(MN interacting with Cryptococcus neoformans: Primary", + "dependence on direct (antibody independent) ictivation of the alternate pathway of", + "complement (C). Amer Rev Resp Dis April, 1979.", + "Takiff HE, Hoidal JR, Repine JE, and Fox RB: Search for different subpopulations of", + "alveolar macrophages(AM) Study of AM kir using tritiated thymidune. Amer", + "Rev Resp Dis April 1979.", + "Hoidal JR and Repine JE: A congenital defect in human alveolar macrophage(AM) function", + "Absence of increased (0,) uptake, superoxide anion(0,-) production, and glucose", + "oxidetion by AM from a patient with chronic granulomatous disease(CGD) Amer Rev", + "Resp Dis April, 1979.", + "Hoidal JR, Fox RB, Takiff HE, and Repine JE: Alveolar macrophages(AM) from young", + "asymptomatic cigarette smokers use equal amounts of oxygen(0,1 and glucose (1-14c),", + "but smoker AM make more superoxide anion(0,-). Amer Rev Resp Dis, April, 1979.", + "Source: https://www.industrydocuments.ucsf.edu/docs/gmnv0215" + ] + } + ] +} \ No newline at end of file