Biomedical subjects

P A Bromberg

Publications and source records attributed to P A Bromberg.

At least 19 recordsLinked to original sources

PubMed2001

Effect of antioxidant supplementation on ozone-induced lung injury in human subjects.

To determine whether antioxidants can influence human susceptibility to ozone (O(3))-induced changes in lung function and airway inflammation, we placed 31 healthy nonsmoking adults (18 to 35 yr old) on a diet low in ascorbate for 3 wk. At 1 wk, subjects were exposed to filtered air for 2 h while exercising (20 L/min/m(2)), and then underwent bronchoalveolar lavage (BAL) and were randomly assigned to receive either a placebo or 250 mg of vitamin C, 50 IU of alpha-tocopherol, and 12 oz of vegetable cocktail daily for 2 wk. Subjects were then exposed to 0.4 ppm O(3) for 2 h and underwent a second BAL. On the day of the O(3) exposure, supplemented subjects were found to have significantly increased levels of plasma ascorbate, tocopherols, and carotenoids as compared with those of the placebo group. Pulmonary function testing showed that O(3)-induced reductions in FEV(1) and FVC were 30% and 24% smaller, respectively, in the supplemented cohort. In contrast, the inflammatory response to O(3) inhalation, as represented by the percent neutrophils and the concentration of interleukin-6 recovered in the BAL fluid at 1 h after O(3) exposure was not different for the two groups. These data suggest that dietary antioxidants protect against O(3)-induced pulmonary function decrements in humans.

Adult↗

PubMed1999

Discordant organ laterality in monozygotic twins with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormal ciliary structure and function, impaired mucociliary clearance, and chronic middle ear, sinus, and lung disease. PCD is associated with situs inversus in approximately 50% of the patients. One proposed explanation for this relationship is that normal ciliary function plays a role in normal organ orientation, whereas organ orientation in PCD is a random event because of dysfunctional cilia in early embryonic development. Another hypothesis for the association between PCD and situs inversus is that mutated genes in PCD not only cause defective cilia, but are also linked to the control of organ laterality, such that abnormalities in this molecular pathway result in random left-right asymmetry. We report on a set of monozygotic twin women with PCD. In both patients, deficiency of the inner dynein arms was noted on ciliary ultrastructural analysis, associated with a clinical syndrome of bronchiectasis, chronic sinusitis, and middle ear disease. One of the twins has situs solitus, the other has situs inversus totalis. DNA analysis confirmed that the twins are monozygotic. This is consistent with the hypothesis that situs inversus occurring in patients with primary ciliary dyskinesia is a random but "complete" event in the fetal development of patients with PCD.

Adult↗

PubMed1999

Cellular and biochemical response of the human lung after intrapulmonary instillation of ferric oxide particles.

Bronchoalveolar lavage (BAL) was used to sample lung cells and biochemical components in the lung air spaces at various times from 1 to 91 d after intrapulmonary instillation of 2.6 microm-diameter iron oxide particles in human subjects. The instillation of particles induced transient acute inflammation during the first day post instillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages as well as increased amounts of protein, lactate dehydrogenase, and interleukin-8 in BAL fluids. This response was subclinical and was resolved within 4 d PI. A similar dose-dependent response was seen in rats 1 d after intratracheal instillation of the same particles. The particles contained small amounts of soluble iron (240 ng/mg) and possessed the capacity to catalyze oxidant generation in vitro. Our findings indicate that the acute inflammation after particle exposure may, at least partially, be the result of oxidant generation catalyzed by the presence of residual amounts of ferric ion, ferric hydroxides, or oxyhydroxides associated with the particles. These findings may have relevance to the acute health effects associated with increased levels of ambient particulate air pollutants.

Adult↗

PubMed1998

Activation of MAPKs in human bronchial epithelial cells exposed to metals.

We have previously shown that in vitro exposure to metallic compounds enhances expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha in human bronchial epithelial cells. To characterize signaling pathways involved in metal-induced expression of inflammatory mediators and to identify metals that activate them, we studied the effects of As, Cr, Cu, Fe, Ni, V, and Zn on the mitogen-activated protein kinases (MAPK) extracellular receptor kinase (ERK), c-Jun NH2-terminal kinase (JNK), and P38 in BEAS cells. Noncytotoxic concentrations of As, V, and Zn induced a rapid phosphorylation of MAPK in BEAS cells. Activity assays confirmed marked activation of ERK, JNK, and P38 in BEAS cells exposed to As, V, and Zn. Cr and Cu exposure resulted in a relatively small activation of MAPK, whereas Fe and Ni did not activate MAPK under these conditions. Similarly, the transcription factors c-Jun and ATF-2, substrates of JNK and P38, respectively, were markedly phosphorylated in BEAS cells treated with As, Cr, Cu, V, and Zn. The same acute exposure to As, V, or Zn that activated MAPK was sufficient to induce a subsequent increase in IL-8 protein expression in BEAS cells. These data suggest that MAPK may mediate metal-induced expression of inflammatory proteins in human bronchial epithelial cells.

Activating Transcription Factor 2↗

PubMed1998

Nociceptive mechanisms modulate ozone-induced human lung function decrements.

We have previously suggested that ozone (O3)-induced pain-related symptoms and inhibition of maximal inspiration are due to stimulation of airway C fibers (M. J. Hazucha, D. V. Bates, and P. A. Bromberg. J. Appl. Physiol. 67: 1535-1541, 1989). If this were so, pain suppression or inhibition by opioid-receptor agonists should partially or fully reverse O3-induced symptomatic and lung functional responses. The objectives of this study were to determine whether O3-induced pain limits maximal inspiration and whether endogenous opioids contribute to modulation of the effects of inhaled O3 on lung function. The participants in this double-blind crossover study were healthy volunteers (18-59 yr) known to be "weak" (WR; n = 20) and "strong" O3 responders (SR; n = 42). They underwent either two 2-h exposures to air or two 2-h exposures to 0. 42 parts/million O3 with moderate intermittent exercise. Immediately after post-O3 spirometry, the WR were randomly given either naloxone (0.15 mg/kg iv) or saline, whereas SR randomly received either sufentanil (0.2 microgram/kg iv) or saline. O3 exposure significantly (P < 0.001) impaired lung function. In SR, sufentanil rapidly, although not completely, reversed both the chest pain and spirometric effects (forced expiratory volume in 1 s; P < 0.0001) compared with saline. Immediate postexposure administration of saline or naloxone had no significant effect on WR. Plasma beta-endorphin levels were not related to an individual's O3 responsiveness. Cutaneous pain variables showed a nonsignificant weak association with O3 responsiveness. These observations demonstrate that nociceptive mechanisms play a key role in modulating O3-induced inhibition of inspiration but not in causing lack of spirometric response to O3 exposure in WR.

Adolescent↗

PubMed1998

Retention and intracellular distribution of instilled iron oxide particles in human alveolar macrophages.

Bronchoalveolar lavage (BAL) was used to sample retention of particles within the alveolar macrophage (AM) compartment at various times from 1 to 91 d following intrapulmonary instillation of 2. 6-microm-diameter iron oxide (Fe2O3) particles in human subjects. Particles were cleared from the lavagable AM compartment in a biphasic pattern, with a rapid-phase clearance half-time of 0.5 d and long-term clearance half-time of 110 d, comparable to retention kinetics determined by more traditional methods. The intracellular distribution of particles within lavaged AMs was similar in bronchial and alveolar BAL fractions. AMs with high intracellular particle burdens disappeared from the lavagable phagocytic AM population disproportionately more rapidly (shorter clearance half-time) than did AMs with lower particle burdens, consistent with the occurrence of a particle redistribution phenomenon as previously described in similar studies in rats. The rates of AM disappearance from the various particle burden categories was generally slightly slower in bronchial fractions than in alveolar fractions. The instillation of particles induced a transient acute inflammatory response at 24 h postinstillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages in BAL fluids. This response was subclinical and was resolved within 4 d PI.

Administration, Inhalation↗

PubMed1998

Rodent models of cardiopulmonary disease: their potential applicability in studies of air pollutant susceptibility.

The mechanisms by which increased mortality and morbidity occur in individuals with preexistent cardiopulmonary disease following acute episodes of air pollution are unknown. Studies involving air pollution effects on animal models of human cardiopulmonary diseases are both infrequent and difficult to interpret. Such models are, however, extensively used in studies of disease pathogenesis. Primarily they comprise those developed by genetic, pharmacologic, or surgical manipulations of the cardiopulmonary system. This review attempts a comprehensive description of rodent cardiopulmonary disease models in the context of their potential application to susceptibility studies of air pollutants regardless of whether the models have been previously used for such studies. The pulmonary disease models include bronchitis, emphysema, asthma/allergy, chronic obstructive pulmonary disease, interstitial fibrosis, and infection. The models of systemic hypertension and congestive heart failure include: those derived by genetics (spontaneously hypertensive, Dahl S. renin transgenic, and other rodent models); congestive heart failure models derived by surgical manipulations; viral myocarditis; and cardiomyopathy induced by adriamycin. The characteristic pathogenic features critical to understanding the susceptibility to inhaled toxicants are described. It is anticipated that this review will provide a ready reference for the selection of appropriate rodent models of cardiopulmonary diseases and identify not only their pathobiologic similarities and/or differences to humans but also their potential usefulness in susceptibility studies.

Air Pollutants↗

PubMed1997

Disruption of protein tyrosine phosphate homeostasis in bronchial epithelial cells exposed to oil fly ash.

Residual oil fly ash (ROFA) is a toxic air pollutant that we have previously shown induces inflammatory mediator expression in human bronchial epithelial cells. To identify intracellular signaling mechanisms activated by ROFA, we studied its effect on protein tyrosine phosphate metabolism in the human bronchial epithelial cell line BEAS. Noncytotoxic levels of ROFA induced significant dose- and time-dependent increases in protein tyrosine phosphate levels in BEAS cells. ROFA-induced increases in protein phosphotyrosines were associated with its soluble fraction and were mimicked by vanadyl [V(IV)]- and vanadate [V(V)]-containing solutions. Ferrous, ferric, and nickel (II) ion solutions failed to increase phosphotyrosine levels. Tyrosine phosphatase activity, which was known to be inhibited by vanadium ions, was markedly diminished after ROFA treatment. Tyrosine kinase activity was unaffected. We conclude that ROFA exposure induces vanadium ion-mediated inhibition of tyrosine phosphatase activity, leading to accumulation of protein phosphotyrosines in BEAS cells. These findings demonstrate that ROFA exposure disrupts protein tyrosine phosphate homeostasis in BEAS cells and suggest a possible mechanism that leads to increased synthesis of proinflammatory proteins in airway epithelial cells exposed to PM10.

Air Pollutants↗

PubMed1997

Epithelial cell-conditioned media inhibits degranulation of the RBL-2H3 rat mast cell line.

The effect of epithelial cells on mast cell responses was investigated by examination of degranulation of the rat mast cell line RBL-2H3 after overnight culture in media conditioned by the BEAS-2B human bronchial epithelial cell line [epithelial cell-conditioned media (ECM)]. These studies indicate that BEAS-2B cells secrete an inhibitor(s) of immunoglobulin E and A-23187-mediated degranulation of the RBL-2H3 cell line. The inhibitory activities of ECM are recovered after filtration through a 3-kDa cutoff filter. Pharmacological inhibition of cyclooxygenase in the BEAS-2B cells before preparation of ECM has no effect on subsequent inhibition of mast cell degranulation by ECM. However, cycloheximide treatment of the BEAS-2B cells before the conditioning process does preclude development of mast cell inhibitor activity in ECM, suggesting that this activity depends on protein synthesis. The effects of ECM on mast cell function are reversible, demonstrating that these effects do not result from overt cytotoxicity. Finally, media conditioned by primary cultures of human respiratory epithelial cells, but not fibroblasts, influence RBL-2H3 degranulation in a manner similar to ECM, suggesting that secretion of mast cell inhibitors may be somewhat unique to epithelial cells.

Animals↗

PubMed1996

Induction of prostaglandin H synthase 2 in human airway epithelial cells exposed to residual oil fly ash.

Exposure to ambient air containing respirable particulate matter at concentrations below the current National Ambient Air Quality Standard has been associated with increased rates of pulmonary-related morbidity and mortality. To identify mechanisms involved in pulmonary responses to such exposure, we studied the effects of the emission source particulate air pollutant residual oil fly ash (ROFA) on prostaglandin metabolism in cultured human airway epithelial cells. Epithelial cells exposed to ROFA for 24 hr secreted substantially increased amounts of the prostaglandin H synthase (PHS) products prostaglandins E2 and F2 alpha. The ROFA-induced increase in prostaglandin synthesis was correlated with a marked increase in PHS activity. Western blots showed that ROFA exposure induced dose-dependent increases in PHS2 protein levels. Reverse transcriptase-PCR analyses demonstrated accompanying increases in PHS2 mRNA which were evident by 2 hr of continuous exposure. In contrast, expression of PHS1 was not affected by ROFA treatment of airway epithelial cells. There were no alterations in arachidonic acid release, incorporation, or availability in ROFA-exposed cells. These data show that exposure to ROFA induces PHS2 expression, leading to increased prostaglandin synthesis in cultured airway epithelial cells. These findings suggest that prostaglandins may play a role in the toxicology of air pollution particle inhalation.

Air Pollutants↗

PubMed1996

Effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes.

Inhalation of O3 causes airways neutrophilic inflammation accompanied by other changes including increased levels of cyclo-oxygenase products of arachidonic acid in bronchoalveolar lavage fluid (BALF). Ozone O3 exposure also causes decreased forced vital capacity (FVC) and forced expiratory volume after 1 s (FEV(1)), associated with cough and substernal pain on inspiration, and small increases in specific airway resistance (SRAW). The spirometric decrements are substantially blunted by pretreatment with indomethacin. Since the O3-induced decrement in FVC is due to involuntary inhibition of inspiration, a role for stimulation of nociceptive respiratory tract afferents has been suggested and cyclo-oxygenase products have been hypothesized to mediate this stimulation. However, the relation (if any) between the O3-induced neutrophilic airways inflammation and decreased inspiratory capacity remains unclear. We studied the effects of pharmacologic inhibition of O3-induced spirometric changes on the inflammatory changes. Each of ten healthy men was exposed twice (5-week interval) to 0.4 ppm O3 for 2 h, including 1 h of intermittent exercise (ventilation 601*min(-1)). One-and-a-half hours prior to and midway during each exposure the subject ingested 800 mg and 200 mg, respectively, of the non-steroidal anti-inflammatory drug ibuprofen (IBU), or placebo [PLA (sucrose)], in randomized, double-blind fashion. Spirometry and body plethysmography were performed prior to drug administration, and before and after O3 exposure. Immediately following postexposure testing, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed. Neither IBU nor PLA administration changed pre-exposure lung function. O3 exposure (with PLA) caused a significant 17 percent mean decrement in FEV(1) (P <0.01) and a 56 percent increase in mean SRAW. Following IBU pretreatment, O3 exposure induced a significantly lesser mean decrement in FEV(1) (7 percent) but still a 50 percent increase in mean SRAW. IBU pretreatment significantly decreased post-O3 BAL levels of prostaglandin E2 (PGE2) by 60.4 percent (P <0.05) and thromboxane B(2) (TxB(2)) by 25.5 percent (P <0.05). Of the proteins, only interleukin-6 was significantly reduced (45 percent, P <0.05) by IBU as compared to PLA pretreatment. As expected, O3 exposure produced neutrophilia in BALF. There was, however, no effect of IBU on this finding. None of the major cell types in the BALF differed significantly between pretreatments. We found no association between post-exposure changes of BALF components and pulmonary function decrements. We conclude that IBU causes significant inhibition of O3-induced increases in respiratory tract PGE(2) and TxB(2) levels concomitant with a blunting of the spirometric response. This is consistent with the hypothesis that the products of AA metabolism mediate inhibition of inspiration. However, IBU did not alter the modest SRAW response to O3.

Adult↗

PubMed1995

Ozone-induced human respiratory dysfunction and disease.

Exercising volunteers exposed in chambers to as little as 80 ppb O3 for several hours exhibit impaired lung function and irritative lower airway symptoms. Comparable changes occur among children and young adults exposed to summer smog containing O3. Intensity of the response is reproducible but varies widely among individuals. The (reversible) decrements in vital capacity are due to involuntary inhibition of deep inspiration probably mediated by nociceptive bronchial C-fibers that may be stimulated by local prostaglandin release, and can be modulated by appropriate pharmacologic agents. A second characteristic response to low O3 levels is mucosal neutrophilic inflammation probably mediated by phospholipid-derived products and by epithelial cell-derived chemokines and cytokines, but poorly correlated with lung function changes. Fluctuations in ambient O3 levels are associated with acute respiratory health effects in exposed populations but concomitant acid aerosol pollution is an important confounder. Whether irreversible impairment of lung function occurs among residents of chronically high ozone-pollution areas is debated.

Adult↗

PubMed1995

Bronchoscopic determination of ozone uptake in humans.

Measurements of ozone uptake efficiency in the human respiratory tract provide critical information toward understanding ozone dose-response characteristics. We measured ozone uptake efficiency by different regions of the respiratory tract between the mouth and bronchus intermedius in 10 healthy, resting, nonsmoking male and female subjects. The distal end of a bronchoscope was sequentially positioned at the bronchus intermedius (BI), main carina (CAR), upper trachea, and above the vocal cords. Ozone concentration was measured continuously at each sight using a rapid-responding ozone analyzer. During sampling subjects breathed through a mouthpiece connected to a pneumotachograph at a paced rate of 12 breaths/min. Integration of the product of the flow and ozone concentrations during inspiration and expiration provided the ozone mass passing each anatomic location during each phase of respiration. On inspiration the uptake efficiencies of ozone by structures between the mouth and each location j (Em-j) were 0.176 +/- 0.037 (SE), 0.271 +/- 0.024, 0.355 +/- 0.030, and 0.325 +/- 0.031 for above the vocal cords, upper trachea, CAR, and BI, respectively. A significant effect of location on Em-j was found by analysis of variance (P < 0.0002). Pairwise comparisons showed that Em-j increased as the lung penetration increased except between CAR and BI, which was not significantly different.

Administration, Inhalation↗

PubMed1994

Prediction of carboxyhemoglobin formation due to transient exposure to carbon monoxide.

Fifteen men were exposed to 6,683 ppm C18O for 3.09-6.65 min. Arterial and antecubital vein blood samples were drawn at 1-min intervals beginning at the start of C18O inhalation and ending 10 min later. Simultaneously, alveolar ventilation was calculated from the measured values of minute ventilation and dead space. All other parameters of the Coburn-Forster-Kane equation (CFKE), except the Haldane affinity ratio, were measured separately in each subject. Means of CFKE predictions of increases in venous HbCO (delta HbCO) in samples collected approximately 2 min after cessation of exposure were accurate, but the range in errors of prediction for individual subjects was +/- 3.8% HbCO, depending on the time after exposure cessation. Increases in venous and arterial HbCO were inaccurately predicted during and immediately after HbCO formation, however. Venous blood was overestimated during CO uptake because of a delayed appearance of HbCO. Individual subjects differed markedly in the degree of delay of HbCO appearance in venous blood. Arterial delta HbCO was consistently underestimated either by the CFKE or by predictions based on venous blood samples. Thus, exposure of such organs as brain or heart to HbCO may be substantially higher than expected during transient high-level CO exposure.

Adolescent↗

PubMed1994

Effect of regional circulation patterns on observed HbCO levels.

In an earlier experiment, we briefly exposed 15 young men to high levels of CO while simultaneously monitoring arterial and peripheral venous HbCO levels. The arterial HbCO levels were considerably higher than the venous levels during the CO exposure. Furthermore, great variation in the difference between arterial and venous HbCO levels was observed, with the maximal difference for each subject ranging from 2.3 to 12.1% HbCO. In the present paper, we suggest an explanation for the observed differences between arterial and venous HbCO on the basis of the regional circulation of the forearm, where both samples were taken. Because regional circulation patterns are known to vary with physical training, the differences in physical training between subjects may account for the observed variation. An expanded model was derived from the Coburn-Forster-Kane equation, which reflects the above hypothesis. Most of the parameter values for the expanded model were measured on individual subjects. Literature values were used for other parameters. Two parameters were estimated using five of the subjects and were then used in the predictions of the expanded model for the remaining subjects.

Arteries↗

PubMed1994

Lung function response of healthy women after sequential exposures to NO2 and O3.

Since NOx emissions bear a precursor-product relation with ambient ozone (O3) levels, the sequence of peak ambient concentrations is first nitrogen dioxide (NO2) followed later in the day by ozone (O3). We ascertained whether preliminary exposure to 0.6 parts per million (ppm) NO2 would affect the lung function response to subsequent exposure to 0.3 ppm O3. Twenty-one healthy young nonsmoking women (18 to 35 yr of age) underwent two sets of exposures on two different days separated by a minimum of 2 wk. On one day, subjects were exposed to air for 2 h followed 3 h later by a 2-h exposure to O3. On the other day, the first exposure was to NO2; order of the days was randomized. During each exposure subjects intermittently exercised, alternating 15 min of rest with 15 min of exercise (Ve approximately 40 L/min). Spirometry was performed before the first exposure and at 1-h intervals until the end of the 2-h (O3) exposure. Plethysmography measurements were made before and after NO2 and O3 exposures. Nonspecific airway reactivity (AR) was determined at least 1 wk prior to the first exposure and following each O3 exposure. AR to methacholine (MCh) was expressed as dose required to decrease FEV1 by 10% (PD10FEV1). Nitrogen dioxide exposure alone did not reduce FEV1 but did significantly enhance O3-induced spirometric changes. No significant effects were observed in plethysmography. On both exposure days, the median PD10FEV1 was significantly reduced (p < 0.05) from control PD10FEV1 (14.3 mg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Role of tachykinins in ozone-induced acute lung injury in guinea pigs.

To examine the hypothesis that the acute reversible changes caused by ozone (O3) exposure are mediated by tachykinin release, guinea pigs were depleted of tachykinins by use of repeated capsaicin (CAP) injections before O3 exposure in an attempt to prevent O3-induced functional changes. Unexpectedly, CAP pretreatment caused divergent results in the functional responses to O3. Ventilatory measurements obtained from CAP-pretreated O3-exposed (CAP-O3) animals were exacerbated rather than diminished compared with the effects of O3 alone. Similarly, lavage fluid protein accumulation was enhanced in the CAP-O3 group compared with the O3-exposed group. In better agreement with our initial hypothesis, the CAP-O3 group was less responsive than the O3-exposed animals to histamine aerosol challenge. Additionally, Evans blue dye accumulation, a hallmark of tachykinin release, was increased in O3-exposed animals and was partially blocked in the CAP-O3 group. These data suggest that tachykinin-containing sensory fibers are unlikely to mediate the acute effects of O3 exposure on tidal breathing and lavage fluid protein accumulation but may play a role in causing post-O3 airway hyperreactivity and protein extravasation into the trachea.

Animals↗

PubMed1993

Predictors of individual differences in acute response to ozone exposure.

The purpose of this study was to identify personal characteristics that predict individual differences in acute FEV1 response to ozone exposure. Response and predictor data were collected on 290 white male volunteers 18 to 32 yr of age who were each exposed to one of six concentrations of ozone between 0.0 and 0.40 part per million. The sample was divided into an exploratory sample of 96 and a confirmatory sample of 194 subjects. Exploratory analysis indicated that ozone, age, and several other variables explained a significant proportion of the variance in response. In the confirmatory sample, only age and ozone concentration predicted FEV1 decrement. For the combined sample ozone explained 31% of the variance, with age accounting for an additional 4%. The model predicted a decreasing response with increasing age for all nonzero ozone concentrations. For exposure to 0.40 ppm, the model predicts decrements in FEV1 of 1.07 and 0.47 L for 18- and 30-yr-old subjects, respectively. We concluded that for white male subjects age was a significant predictor of response, with older subjects being less responsive to ozone. Furthermore, we demonstrated that exploratory analysis without control of type I statistical error rates may result in apparent findings that cannot be replicated.

Adolescent↗