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Biomedical subjects

G G Murthy

Publications and source records attributed to G G Murthy.

At least 19 recordsLinked to original sources
PubMed2001

Inhalation delivery of proteins from ethanol suspensions.

To circumvent inherent problems associated with pulmonary administration of aqueous-solution and dry-powder protein drugs, inhalation delivery of proteins from their suspensions in absolute ethanol was explored both in vitro and in vivo. Protein suspensions in ethanol of up to 9% (wt/vol) were readily aerosolized with a commercial compressor nebulizer. Experiments with enzymic proteins revealed that nebulization caused no detectable loss of catalytic activity; furthermore, enzyme suspensions in anhydrous ethanol retained their full catalytic activity for at least 3 weeks at room temperature. With the use of Zn(2+)-insulin, conditions were elaborated that produced submicron protein particles in ethanol suspensions. The latter (insulin/EtOH) afforded respirable-size aerosol particles after nebulization. A 40-min exposure of laboratory rats to 10 mg/ml insulin/EtOH aerosols resulted in a 2-fold drop in the blood glucose level and a marked rise in the serum insulin level. The bioavailability based on estimated deposited lung dose of insulin delivered by inhalation of ethanol suspension aerosols was 33% (relative to an equivalent s.c. injection), i.e., comparable to those observed in rats after inhalation administration of dry powder and aqueous solutions of insulin. Inhalation of ethanol in a relevant amount/time frame resulted in no detectable acute toxic effects on rat lungs or airways, as reflected by the absence of statistically significant inflammatory or allergic responses, damage to the alveolar/capillary barrier, and lysed and/or damaged cells.

Administration, Inhalation↗
PubMed2001

Tumor necrosis factor receptor 2 contributes to ozone-induced airway hyperresponsiveness in mice.

UNLABELLED: The purpose of this study was to determine whether tumor necrosis factor (TNF) contributes to airway hyperresponsiveness (AHR) and migration of polymorphonuclear leukocytes (PMN) into the airways following exposure to ozone (O(3)). Wild-type mice, TNF p55 or p75 receptor knockout mice (p55 TNFR -/- and p75 TNFR -/-), as well as double receptor knockout mice (p55/p75 TNFR -/-), were exposed to O(3). Three hours after cessation of O(3), airway responses to inhaled methacholine were determined by whole body plethysmography using changes in enhanced pause (Penh) as an index of airway narrowing. In wild-type mice, O(3) exposure (0.5 ppm, 3 h) caused a significant increase in airway responsiveness as indicated by a 1.2 log leftward shift in the methacholine dose- response curve. In contrast, in p55/p75 TNFR -/- mice, O(3) caused only a 0.5 log shift in the dose-response curve (p < 0.05 compared with wild-type). Similar results were obtained in p75 TNFR -/- mice. In contrast, O(3)-induced airway hyperresponsiveness was not different in WT and p55 TNFR -/- mice. During O(3) exposure (1 pm, 3 h), minute ventilation (V E) decreased by 64 +/- 4% in wild-type, but only 24 +/- 5% in p55/p75 TNFR -/- mice, indicating that despite their reduced O(3)-induced AHR, the TNFR-deficient mice actually inhaled a greater dose of O(3). Similar results were obtained in p75 -/- mice, whereas changes in V E induced by O(3) were the same in wild-type and p55 -/- mice. PMN numbers in bronchoalveolar lavage fluid recovered 21 h after cessation of exposure to O(3) (2 ppm, 3 h) were significantly increased compared with after air exposure but were not different in wild-type and p55/p75 TNFR -/- mice. Our results indicate that TNF contributes to the AHR but not the PMN emigration induced by acute O(3) exposure. KEYWORDS: whole body plethysmography; polymorphonuclear leukocytes; minute ventilation; knockout mice; methacholine

Administration, Inhalation↗
PubMed2001

Ozone causes lipid peroxidation but little antioxidant depletion in exercising and nonexercising hamsters.

Ozone (O(3)), a major component of urban air pollution, is a strong oxidizing agent that can cause lung injury and inflammation. In the present study, we investigated the effect of inhalation of O(3) on levels of F(2)-isoprostanes in bronchoalveolar lavage fluid (BALF) and on levels of antioxidants in the BALF and plasma of hamsters. Because antioxidants, including urate, ascorbate, GSH, and vitamin E, defend the lungs by reacting with oxidizing agents, we expected to find a decrease in antioxidant levels after O(3) exposure. Similarly, we expected an increase in the levels of F(2)-isoprostanes, which are lipid peroxidation products. Exposure to 1.0 or 3.0 parts/million (ppm) O(3) for 6 h resulted in an increase in BALF neutrophil numbers, an indicator of acute inflammation, as well as elevation of BALF F(2)-isoprostanes. The higher dose of O(3) caused an increase in the BALF level of urate and a decrease in the plasma level of ascorbate, but 1.0 ppm O(3) had no effect on BALF or plasma antioxidant levels. Exposure to 0.12 ppm O(3) had no effect on BALF neutrophils or F(2)-isoprostanes nor on BALF and plasma antioxidants. We also investigated the effect of O(3) exposure of hamsters during exercise on F(2)-isoprostane and antioxidant levels. We found that exposure to 1.0 ppm O(3) during 1 h of exercise on a laddermill increased BALF levels of F(2)-isoprostanes but had no effect on BALF neutrophils or on BALF and plasma antioxidants. These results indicate that O(3) induces inflammation and biomolecule oxidation in the lungs, whereas extracellular antioxidant levels are relatively unchanged.

Animals↗
PubMed2001

Effects of combined ozone and air pollution particle exposure in mice.

Epidemiologic studies indicate that ozone (O3*) and air pollution particles can exacerbate asthma symptoms. We investigated whether coexposure to inhaled particles and O3 causes a synergistic effect on airway responsiveness and allergic inflammation in a murine (BALB/c) model of ovalbumin (OVA)-induced asthma. Half of the mice were sensitized by intraperitoneal injection of OVA and then exposed to OVA aerosol on 3 successive days to create the asthmatic phenotype; the other half were sensitized to OVA and exposed to phosphate-buffered saline (PBS) to create the nonasthmatic control group. On the same 3 days that the OVA or PBS challenge was administered, mice were further divided into groups that were exposed for 5 hours to concentrated ambient particles (CAPs; mass values ranging from 63 to 1,569 microg/m3 for 1 day's exposure), 0.3 ppm O3, both, or neither (n > or = 61 total mice per exposure group for all 12 experiments). Whole-body plethysmography was used to measure airway responsiveness after challenge with aerosolized methacholine (MCh). Enhanced pause (Penh), an index that closely correlates with pulmonary resistance (Hamelmann et al 1997), was measured daily in each mouse immediately after pollutant exposure and, for 7 of the 12 experiments (n > or = 36/exposure group), beginning 24 hours after the final OVA or PBS challenge. Using several complementary statistical models, we found that exposure to CAPs alone caused a small but significant increase in Penh in both normal and asthmatic mice immediately after exposure (an increase of approximately 1% per 100-microg/m3 increase in CAPs). No increase in Penh was found in animals exposed to O3 alone or to filtered air. Compared with control animals, no combination of exposure atmosphere plus asthma produced a synergistic effect on Penh. By 24 hours after the last OVA or PBS challenge, any enhanced response induced by pollutant exposure had declined to control levels. The pollutant exposures did not significantly increase airway inflammation (assessed by bronchoalveolar lavage [BAL] fluid analysis beginning 24 or 48 hours after the final OVA or PBS challenge). Because CAPs are a heterogeneous mixture of particles, elemental analysis was conducted and associations between specific elemental groupings (present in daily samples) and airway responsiveness were analyzed. This analysis showed that increased Penh in asthmatic mice exposed to CAPs plus O3 was associated with the AlSi fraction of CAPs. No such association was found in control mice or in asthmatic mice not exposed to O3. We conclude that CAPs exposure causes an immediate, short-lived (< 24-hour), small increase in airway responsiveness in mice and that changes in airway physiology are correlated with specific elements found within the particle mixture.

Air Pollutants↗
PubMed2000

Ventilatory responses to ozone are reduced in immature rats.

During ozone (O(3)) exposure, adult rats decrease their minute ventilation (VE). To determine whether such changes are also observed in immature animals, Sprague-Dawley rats, aged 2, 4, 6, 8, or 12 wk, were exposed to O(3) (2 ppm) in nose-only-exposure plethysmographs. Baseline VE normalized for body weight decreased with age from 2.1 +/- 0.1 ml. min(-1). g(-1) in 2-wk-old rats to 0. 72 +/- 0.03 ml. min(-1). g(-1) in 12-wk-old rats, consistent with the higher metabolic rates of younger animals. In adult (8- and 12-wk-old) rats, O(3) caused 40-50% decreases in VE that occurred primarily as the result of a decrease in tidal volume. In 6-wk-old rats, O(3)-induced changes in VE were significantly less, and in 2- and 4-wk-old rats, no significant changes in VE were observed during O(3) exposure. The increased baseline VE and the smaller decrements in VE induced by O(3) in the immature rats imply that their delivered dose of O(3) is much higher than in adult rats. To determine whether these differences in O(3) dose influence the extent of injury, we measured bronchoalveolar lavage protein concentrations. The magnitude of the changes in bronchoalveolar lavage induced by O(3) was significantly greater in 2- than in 8-wk-old rats (267 +/- 47 vs. 165 +/- 22%, respectively, P < 0.05). O(3) exposure also caused a significant increase in PGE(2) in 2-wk-old but not in adult rats. The results indicate that the ventilatory response to O(3) is absent in 2-wk-old rats and that lack of this response, in conjunction with a greater specific ventilation, leads to greater lung injury.

Animals↗
PubMed2000

Inhaled concentrated ambient particles are associated with hematologic and bronchoalveolar lavage changes in canines.

Pulmonary inflammatory and hematologic responses of canines were studied after exposure to concentrated ambient particles (CAPs) using the Harvard ambient particle concentrator (HAPC). For pulmonary inflammatory studies, normal dogs were exposed in pairs to either CAPs or filtered air (paired studies) for 6 hr/day on 3 consecutive days. For hematologic studies, dogs were exposed for 6 hr/day for 3 consecutive days with one receiving CAPs while the other was simultaneously exposed to filtered air; crossover of exposure took place the following week (crossover studies). Physicochemical characterization of CAPs exposure samples included measurements of particle mass, size distribution, and composition. No statistical differences in biologic responses were found when all CAPs and all sham exposures were compared. However, the variability in biologic response was considerably higher with CAPs exposure. Subsequent exploratory graphical analyses and mixed linear regression analyses suggested associations between CAPs constituents and biologic responses. Factor analysis was applied to the compositional data from paired and crossover experiments to determine elements consistently associated with each other in CAPs samples. In paired experiments, four factors were identified; in crossover studies, a total of six factors were observed. Bronchoalveolar lavage (BAL) and hematologic data were regressed on the factor scores. Increased BAL neutrophil percentage, total peripheral white blood cell (WBC) counts, circulating neutrophils, and circulating lymphocytes were associated with increases in the aluminum/silicon factor. Increased circulating neutrophils and increased BAL macrophages were associated with the vanadium/nickel factor. Increased BAL neutrophils were associated with the bromine/lead factor when only the compositional data from the third day of CAPs exposure were used. Significant decreases in red blood cell counts and hemoglobin levels were correlated with the sulfur factor. BAL or hematologic parameters were not associated with increases in total CAPs mass concentration. These data suggest that CAPs inhalation is associated with subtle alterations in pulmonary and systemic cell profiles, and specific components of CAPs may be responsible for these biologic responses.

Air Pollutants↗
PubMed2000

Mechanisms of morbidity and mortality from exposure to ambient air particles.

The studies reported here assessed pathophysiologic mechanisms that result from exposure to concentrated ambient particles (CAPs) in animals with and without cardiopulmonary compromise. These studies were carried out to determine the biologic plausibility of epidemiologic observations of increases in particulate air pollution associated with increases in human morbidity and mortality. Dogs were exposed two at a time to CAPs or filtered air via tracheostomy for six hours per day on three consecutive days. The electrocardiogram (ECG) and breathing pattern were recorded continuously, and indicators of inflammation were also assessed. In one experimental design, normal dogs were exposed in pairs to CAPs and subsequently to filtered air or to filtered air and subsequently CAPs (the double CAPs/double sham design). Comparisons were made between the CAPs measurements and each dog's own sham responses. In another design, one dog was exposed to CAPs while the chambermate received a sham exposure; these experiments were followed by crossover of the protocol the subsequent week (the crossover design). Comparisons were made between the CAPs exposure and both the chambermate's sham and each dog's own sham responses. The crossover experiments were conducted in normal animals and in animals who had undergone balloon occlusion of the left anterior descending (LAD) coronary artery to induce myocardial compromise. The effects of CAPs in animals with induced chronic bronchitis were part of the original specific aims; because these studies were not fully pursued, the results are presented only in Appendix A. In normal dogs, analyses of all double CAPs and crossover studies revealed low frequency (LF) and high frequency (HF) powers for heart rate variability (HRV) that were significantly higher for CAPs exposure compared to sham exposure. Variation in day-to-day exposure concentrations, aerosol composition, and pathophysiologic responses were also found. The crossover design, continuous measures of aerosol mass, and biologic responses were incorporated in the development of a statistical model that allowed isolation of changes associated with CAPs from changes due to animal variations. Comparison of individual exposures with this model revealed a range from no response in any measured parameter to statistically significant changes in cardiac autonomic balance, pulmonary air flow, and breathing pattern. On days in which dogs showed statistically significant changes in responses, the findings were consistent in both cardiac and respiratory parameters. Days associated with significant increases in LF and HF HRV, LF/ HF HRV ratio, and heart rate standard deviation (HR SD) were also associated with decreases in average heart rate. These same days had decreases in respiratory frequency, tidal volume, minute volume, and peak flows with corresponding increases in respiratory cycle times and enhanced pause (Pauenh), a measure of bronchoconstriction. These cardiac and respiratory changes suggest an effect mediated via both the sympathetic nervous system and the vagus nerve. Alternatively, days associated with increased heart rate had decreases in the HR SD; decreases or no change in HF and LF HRV; increases in respiratory flows and volumes; and decreases in breathing cycle times, all suggesting only sympathetic nervous system mediation. When all data from the crossover design experiments were assessed with this model, the heart rate and respiratory rate were significantly decreased in relation to both cumulative and actual exposure and the LF HRV, LF/HF HRV ratio, HR SD, and all other respiratory parameters were significantly increased (p < 0.0001 for all). When cardiac data were grouped by days in which the air mass trajectory came from the north or northwest (versus west, south, east, or northeast), significant increases in HR SD and HF HRV and significant decreases in average heart rate were associated with the northwest trajectory. (ABSTRACT TRUNCATED)

Air Pollutants↗
PubMed1999

Effect of welding fume solubility on lung macrophage viability and function in vitro.

It was shown previously that fumes generated from stainless steel (SS) welding induced more pneumotoxicity and were cleared from the lungs at a slower rate than fumes collected from mild steel (MS) welding. These differences in response may be attributed to the metal composition of SS and MS welding fumes. In this study, fumes with vastly different metal profiles were collected during gas metal arc (GMA) or flux-covered manual metal arc (MMA) welding using two different consumable electrodes, SS or MS. The collected samples were suspended in saline, incubated for 24 h at 37 degrees C, and centrifuged. The supernatant (soluble components) and pellets (insoluble particulates) were separated, and their effects on lung macrophage viability and the release of reactive oxygen species (ROS) by macrophages were examined in vitro. The soluble MMA-SS sample was shown to be the most cytotoxic to macrophages and to have the greatest effect on their function as compared to the GMA-SS and GMA-MS fumes. Neither the soluble nor insoluble forms of the GMA-MS sample had any marked effect on macrophage viability. The flux-covered MMA-SS fume was found to be much more water soluble as compared to either the GMA-SS or the GMA-MS fumes. The soluble fraction of the MMA-SS samples was comprised almost entirely of Cr. The small fraction of the GMA-MS sample that was soluble contained Mn with little Fe, while a more complex mixture was observed in the soluble portion of the GMA-SS sample, which contained Mn, Ni, Fe, Cr, and Cu. Data show that differences in the solubility of welding fumes influence the viability and ROS production of macrophages. The presence of soluble metals, such as Fe, Cr, Ni, Cu, and Mn, and the complexes formed by these different metals are likely important in the pulmonary responses observed after welding fume exposure.

Air Pollutants, Occupational↗
PubMed1999

Urban air particulate inhalation alters pulmonary function and induces pulmonary inflammation in a rodent model of chronic bronchitis.

Epidemiological studies have reported increased morbidity in human populations following inhalation of elevated levels of urban particulate matter. These responses are especially prevalent in populations with chronic obstructive pulmonary diseases, including chronic bronchitis. Toxicological studies have reported altered pulmonary function and increased pulmonary inflammation following particulate inhalation in the laboratory setting. However, most of these studies have utilized artificial particles that may not accurately mimic outdoor air pollutant conditions. Few studies have utilized actual urban air particle samples in inhalation studies. In the present study, the effects of inhaled concentrated urban air particulates on pulmonary function and pulmonary inflammation are addressed. Normal rats and rats with chronic bronchitis induced by approximately 200 ppm SO(2) for 6 wk were subsequently subjected to filtered air or concentrated air particles (CAPs). Twelve rats per group in 4 groups (48 rats total) were exposed for 5 h/day for 3 consecutive days. The CAPs aerosol levels were 206, 733, and 607 microg/m(3) (MMAD = 0.18 microm, sigma(g) = 2.9) on days 1, 2, and 3, respectively. Following the final day of exposure, pulmonary function parameters, including peak expiratory flow (PEF), tidal volume (TV), respiratory frequency (RF), and minute volume (MV), were measured and compared to preexposure baseline levels. Twenty-four hours following the final day of exposure, bronchoalveolar lavage was performed for total cell counts, differential cell counts, and total lavage protein levels. Pulmonary responses to CAPs in chronic bronchitic animals indicated a significant increase in tidal volume as well as peak expiratory flow. In CAPs-exposed animals without underlying bronchitis, significantly increased tidal volume was observed. Significant pulmonary inflammation was observed in the CAPs-exposed animals, particularly those with chronic bronchitis. Significant increases in neutrophils, lymphocytes, and total lavage protein were observed. These results suggest two distinct mechanistic responses to inhaled particles: a stress-type pulmonary function response marked by increases in flow and volume, that is, deeper breathing; and acute pulmonary inflammation marked by cellular influx, particularly neutrophils. From these data it is concluded that inhaled urban air particles alter pulmonary breathing parameters and increase pulmonary inflammation.

Air Pollutants↗
PubMed1998

Cigarette smoke induces DNA deletions in the mouse embryo.

Cigarette smoking causes cancer and DNA mutations. However, long-term chronic exposure to smoke is believed to be necessary for carcinogenesis. Here, we investigate the relationship between short-term exposure to smoke and the frequency of deletions in the mouse embryo. Deletions and other genome rearrangements are associated with carcinogenesis and inheritable diseases. The pink-eyed unstable (p(un)) mutation in the C57BL/6J mouse is the result of internal duplication of 70 kb of DNA within the p gene. Spontaneous reversion events in homozygous p(un)/p(un) mice occur by deletion of one copy of the duplicated sequence. Reversion events occurring in the embryonic premelanocytes of the developing fetus give rise to black spots on the gray fur of the offspring after birth. We investigated the effects of exposure of pregnant p(un) mice to cigarette smoke and cigarette smoke condensate (CSC) on the frequency of black spots occurring in the offspring. Pregnant dams were exposed (whole body) to smoke generated by either filtered or unfiltered cigarettes for 4 h, or alternatively, mice were given a 15 mg/kg dose of CSC during their 10th day of gestation. TPM, CO concentration, and plasma nicotine and cotinine levels were determined to characterize the smoke exposure. There was a significant increase in the number of DNA deletions in the embryo as evidenced by spotted offspring in both smoke-exposed groups and in the CSC group. These results suggest that embryos are highly sensitive to the genotoxic activity of cigarette smoke following a single exposure of only 4 h.

Animals↗
PubMed1998

Role of tachykinins in airway responses to ozone in rats.

Previous studies that used neonatal capsaicin (Cap) treatment to ablate C fibers indicate that C fibers act to inhibit lung damage and airway hyperresponsiveness after ozone (O3) exposure in rats. The purpose of this study was to determine 1) the role of tachykinins in these protective effects and 2) whether differences in minute ventilation (VE) during O3 exposure might account for the effect of Cap. In the first study, male Sprague-Dawley rats were exposed to 1 part/million O3 or air for 3 h. Four hours later, a bronchoalveolar lavage (BAL) was performed or airway responsiveness was measured. Rats were treated with CP-99994 and SR-48968, selective neurokinin-1- and -2-receptor antagonists, respectively, or with vehicle (Veh). O3 caused an increase in the number of neutrophils recovered from BAL fluid in both the Veh-treated and tachykinin-receptor antagonist (TKRA)-treated rats, but the number of neutrophils was approximately twofold greater in the TKRA-treated rats. In contrast, TKRA treatment had no effect on baseline pulmonary mechanics or airway responsiveness. After O3 exposure, the number of neutrophils in BAL fluid was also greater in Cap- than in Veh-treated rats. O3 reduced VE in both Veh- and Cap-treated rats, but the response was greater (reduction of 44.7 +/- 3.7 vs. 27.8 +/- 6.8%) and occurred earlier (10 vs. 70 min) in Cap- than in Veh-treated rats (P < 0.02). These results suggest that tachykinins mediate protective effects of C fibers against O3-induced lung inflammation. The results also indicate that the more pronounced effect of O3 on BAL neutrophils in Cap-treated rats is not the result of a greater inhaled dose of O3 resulting from greater VE.

Animals↗
PubMed1992

Epidemic of malaria in Barmer district (Thar desert) of Rajasthan during 1990.

Barmer district of Rajasthan in Thar desert and hitherto a hypoendemic area for malaria came in the grip of a severe malaria epidemic during 1990. The epidemic occurred as an aftermath of floods, preceded by normal rains during 1988 and 1989 after a prolonged drought phase. The epidemic was spread over the whole district including Barmer town. Annual Parasite Incidence (API) and Annual falciparum Incidence (AFI) for the district touched record figures of 17.20 and 5.83 respectively while for the Barmer town they were 36.5 and 14.0 respectively. Out of the eight PHCs, Baitu PHC was the worst affected where the two indices touched all-time high figures of 55.3 and 19.6 per cent respectively. A total of 122 infants were reported positive for malaria, of which 103 were contributed by Baitu PHC alone. Eighty per cent infant positivity was spread over September and November, indicating a high rate of transmission. A total of 47 deaths due to cerebral malaria were reported. However, in view of the high infectivity among infants and paediatric groups there was a strong possibility of deaths among these groups which could not be verified. Entomological findings revealed that a sudden increase in An. culicifacies densities due to extensive breeding potential, as a sequel to floods, activated the transmission, which was maintained at a low level by An. stephensi, predominant in this desert region. Other factors which contributed to the intensity and extent of epidemic were the return of drought-migrated population from malarious areas, low cattle density, malaria non-immune population, inadequate and poor spray coverage and delayed radical treatment. Insecticide adult susceptibility tests revealed a high degree of resistance in An. stephensi against DDT and dieldrin.

Adolescent↗
PubMed1976

Pituitary-testicular axis in patients on lithium therapy.

Plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were studied in 10 patients undergoing lithium therapy. Testosterone levels were below the normal range in 7 of the 10 patients. FSH levels were high in two patients and LH levels were high in one. The effects of lithium on the pituitary-testicular axis are discussed.

Adult↗
PubMed1976

Demonstration of antibodies to testicular basement membrane by immunofluorescence in a patient with multiple primary endocrine deficiencies.

Circulating antibodies directed against testicular basement membrane and germinal cells are demonstrated in a patient with multiple primary endocrine gland deficiencies involving the thyroid, adrenals, testes, and pernicious anemia. Testicular biopsy revealed focal destruction of seminiferous tubules and interstitial fibrosis. The tubular basement membranes showed sharply positive immunofluorescence when stained with the patient's FITC conjugated gamma globulins.

17-Ketosteroids↗