Biomedical subjects
D Christian
Publications and source records attributed to D Christian.
Methacholine responsiveness is not associated with O3-induced decreases in FEV1.
STUDY OBJECTIVE: Controlled human exposure studies have suggested that the National Ambient Air Quality Standard for ozone (O3) may not provide a margin of safety to protect the most susceptible members of the population from adverse health effects. Although the subgroups of the population that are most susceptible to O3 have not been identified, recent work in our laboratory suggested that methacholine responsiveness might be an important determinant of susceptibility to O3. PATIENTS AND METHODS: To test the hypothesis that methacholine responsiveness is correlated with FEV1 response after O3 exposure, we conducted methacholine challenge tests and O3 (0.20 ppm) and filtered air exposures for 4 h with moderate exercise on 66 healthy individuals. RESULTS: Repeated measures analysis of variance demonstrated significant changes in FEV1 (-0.82 +/- 0.63 L), FVC (-0.69 +/- 0.48 L), and specific airway resistance (SRaw) (+1.5 +/- 1.1 L x cm H2O/L/s) across the O3 exposure that persisted after adjusting for responses to air. Baseline PC100 (the concentration of methacholine that caused a doubling of the baseline SRaw) was weakly associated with O3-induced increases in SRaw (F1.54 = 2.85, p = 0.09), but not O3-induced declines in FEV1 or FVC. There was a weak association (r = -0.29) between O3-induced responses for SRaw and FEV1. The FEV1 responses for O3 were weakly associated with the symptoms of cough (r = -0.37), wheeze (r = -0.29), chest pain on deep inspiration (r = -0.31), and shortness of breath (r = -0.37), but not with chest discomfort or sputum production. CONCLUSIONS: Although we were unable to find support for our hypothesis, we found, somewhat surprisingly, that respiratory symptoms were weakly associated or unassociated with FEV1 responses after O3 exposure. This finding implies that individuals may experience adverse effects, ie, respiratory symptoms, without large declines in lung function. Conversely, individuals may suffer large declines in lung function without prominent symptoms and, therefore, may remain in an unhealthy environment despite evidence of toxicity.
Lung epithelial lining fluid T cell subsets defined by distinct patterns of beta 7 and beta 1 integrin expression.
Integrins are heterodimeric cell-surface glycoproteins that mediate cell-cell and cell-matrix adhesion. We previously identified cDNA encoding a novel integrin beta subunit, beta 7, from bronchoalveolar lavage fluid (BALF) leukocytes. The beta 7 subunit protein is now known to associate with at least two integrin alpha subunits on lymphocytes. One beta 7 integrin, alpha 4 beta 7, mediates lymphocyte adhesion to endothelium and to fibronectin. The other known beta 7 integrin, alpha E beta 7, has recently been shown to mediate lymphocyte-epithelial cell adhesion in vitro. We used flow microfluorometry to analyze the expression of alpha 4 beta 7, alpha E beta 7, and other integrins on blood T cells and epithelial lining fluid T cells obtained from five healthy adult volunteers by bronchoalveolar lavage. alpha 4 beta 7 was the predominant beta 7 integrin on blood T cells, whereas alpha E beta 7 was predominant on BALF T cells. BALF T cells could be divided into alpha E beta 7- and alpha E beta 7+ subsets. Between 29 and 61% (mean 42%) of CD3+ T cells were alpha E beta 7+ alpha E beta 7 was more likely to be present on CD8+ T cells (mean 69% alpha E beta 7+) than on CD4+ T cells (mean 29% alpha E beta 7+). The alpha E beta 7- and alpha E beta 7+ BALF T cell subsets were also found to differ in their expression of other integrins.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of nitric acid gas alone or in combination with ozone on healthy volunteers.
Nitric acid (HNO3) is the most prevalent acid air pollutant in the western United States and has the potential to cause adverse respiratory effects through both acidification and oxidation reactions. To study this potential, we measured physiologic (specific airway resistance, SRaw, FEV1, and FVC) and bronchoalveolar lavage (total and differential cell counts, LDH, fibronectin, and total protein) end points in a group of 10 healthy, athletic subjects who were exposed to 500 micrograms/m3 of HNO3 gas or filtered air for 4 h during moderate exercise (ventilatory rate, 40 L/min) and underwent bronchoscopy 18 h later. Under an identical protocol, 10 healthy subjects were exposed to 500 micrograms/m3 of HNO3 gas plus 0.20 ppm ozone (O3) or 0.20 ppm O3 alone to determine if HNO3 might enhance the toxicity of O3. In addition to bronchoalveolar lavage (BAL), we employed the techniques of isolated left mainstem bronchial lavage and bronchial biopsy to determine if proximal airway injury was caused by pollutant exposure and whether there was any correlation with the degree of distal lung injury as assessed by BAL. We found no significant differences in pulmonary function tests or in the cellular or biochemical constituents in either the BAL or the left mainstem lavage fluids between the HNO3 and the air exposures. Similarly, there were no differences in these end points between the HNO3/O3 and the O3 exposures. Furthermore, there were no significant differences in the bronchial biopsy specimens between the HNO3 and air exposures or between the HNO3/O3 and O3 exposures.(ABSTRACT TRUNCATED AT 250 WORDS)
Ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy.
Ozone (O3) is a major constituent of urban air pollution. The acute effects of the inhalation of O3 at ambient or near-ambient concentrations on bronchoalveolar lavage (BAL) end points consistent with a distal lung inflammatory response have been well documented in human subjects. Animal toxicologic studies have shown that the airway is also a major site of O3-induced injury and inflammation. To date, no studies have confirmed this finding in human subjects. Effects of O3 on the proximal airways are not adequately studied by BAL, which is primarily influenced by events occurring in the terminal bronchioles and alveoli. We hypothesized that O3 causes injury and inflammation in the airways in addition to that previously documented to occur in the distal lung. We performed isolated lavage of the left mainstem bronchus and forceps biopsy of the bronchial mucosa in a group of 14 healthy, athletic subjects 18 h after exposure to 0.20 ppm O3 for 4 h during moderate exercise in order to assess this possibility. We followed an identical protocol in a similar group of 12 subjects exposed to filtered air. The mean (SD) total cell count and the lactate dehydrogenase (LDH) concentration in the isolated airway lavage were significantly greater after O3 than after air, 13.9 (20.5) versus 4.9 (5.4) cells/ml x 10(4) and 18.9 (11.2) versus 9.6 (9.0) U/L, respectively. Morphometry (2,070 neutrophils/cm2 of tissue for O3 and 330 neutrophils/cm2 of tissue for air) demonstrated that O3 exposure induced an acute inflammatory cell influx into the airway.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of sequential exposure to acidic fog and ozone on pulmonary function in exercising subjects.
In Southern California coastal regions, morning fog is often acidified by the presence of nitric acid (HNO3). Peak exposure to ozone (O3) usually occurs in the afternoon and evening, after the fog has dissipated. To determine whether fog containing HNO3 might enhance pulmonary responses to O3, we studied a group of healthy, athletic subjects selected for lung function sensitivity to O3. On 3 separate days, the subjects exercised for 2 h in atmospheres containing HNO3 fog (0.5 mg/ml), H2O fog, or clean, filtered air. After a 1-h break, they exercised for an additional 3 h in an atmosphere containing 0.20 ppm O3. Surprisingly, the mean O3-induced decrements in FEV1 and FVC were smaller after exercise in each fog-containing atmosphere than they were after exercise in clean, filtered air. The mean (+/- SEM) O3-induced decrements in FEV1 were 26.4 +/- 5.3% after air, 17.1 +/- 3.7% after H2O fog, and 18.0 +/- 4.3% after HNO3 fog, and in FVC they were 19.9 +/- 4.7% after air, 13.6 +/- 2.8% after H2O fog, and 13.6 +/- 4.2% after HNO3 fog.(ABSTRACT TRUNCATED AT 250 WORDS)
Lack of bronchoconstrictor response to sulfuric acid aerosols and fogs.
Sulfuric acid (H2SO4) is the most common acid air pollutant in the United States and is thought to have adverse respiratory effects. Sulfuric acid exists in polluted air as a dissolved solute in both small (haze) and large (fog) particles. Previous work in our laboratory has failed to demonstrate bronchoconstriction after near ambient, large-particle H2SO4 exposure in subjects with asthma. However, other investigators have found slight but significant changes in lung function following inhalation of small-particle or small-particle, low-relative-humidity (RH) H2SO4 aerosols, leading us to hypothesize that particle size and/or RH may be important variables in acid aerosol exposure. We initially studied the effects of resting inhalation of large-particle (volume median diameter, VMD, approximately equal to 6 microns) and small-particle (VMD approximately equal to 0.4 microns) aerosols with an H2SO4 concentration of 3 mg/m3 through a mouthpiece and found no effect on specific airway resistance (SRaw) or symptom scores. In a second mouthpiece study designed to compare high-RH (100%), large-particle (VMD approximately equal to 6 microns) and low-RH (less than 10%), small-particle (VMD approximately equal to 0.3 microns) aerosols with an H2SO4 concentration of 3 mg/m3, we again found no effect of either aerosol. We then examined the effects of small-particle aerosols inhaled in dry air during moderate exercise. Although breathing low-RH air during exercise provoked increases in SRaw in almost all subjects, this could not be attributed to H2SO4 since low-RH saline aerosol produced a similar result.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid fog-induced bronchoconstriction. The role of hydroxymethanesulfonic acid.
Hydroxymethanesulfonate (HMSA), the bisulfite (HSO3-) adduct of formaldehyde (CH2O), is a common constituent of California acid fogs. HMSA, most stable in a fog pH range of 3 to 5, dissociates at 6.6, the pH of the fluid lining human airways. The dissociation of inhaled HMSA should theoretically generate sulfur dioxide and CH2O, both of which have bronchoconstrictor potential. Thus, we hypothesized that HMSA may have a specific bronchoconstrictor effect independent of its strength as an acid. To determine whether HMSA has such an effect, 19 subjects with mild to moderate asthma were studied using two different protocols. Initially, a mouthpiece study was performed in which 9 subjects, on 2 separate days, inhaled five aerosols containing either sequentially increasing concentrations (0, 30, 100, 300, and 1000 microM) of HMSA in 50 microM sulfuric acid (H2SO4) or 50 microM H2SO4 alone. The subjects inhaled each aerosol for 3 min during tidal breathing at rest. Specific airway resistance (SRaw) was measured before and after each 3-min exposure. There were no significant differences in the mean changes in SRaw among the various aerosol exposures. To confirm this lack of bronchoconstrictor effect of HMSA, we then performed a chamber study in which 10 freely breathing, intermittently exercising subjects were exposed to fog containing either 1 mM HMSA in 5 mM H2SO4 or 5 mM H2SO4 alone for 1 h. SRaw was measured before, during, and at the end of the 1-h exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidity potentiates bronchoconstriction induced by hypoosmolar aerosols.
Naturally occurring fogs are usually hypoosmolar with respect to body fluids and can be quite acidic. Because both hypoosmolarity and acidity can cause bronchoconstriction, we studied whether there was a positive interaction between these stimuli in 12 subjects with asthma. We administered the following aerosols: hypoosmolar saline (30 mOsm) at pH 5.5, 3 hypoosmolar acids (0.005 M H2SO4, 0.01 M HNO3 and a 1:1 mixture of 0.005 M H2SO4 and 0.01 M HNO3, all 30 mOsm) at pH 2, and isoosmolar 0.005 M H2SO4 (300 mOsm) at pH 2. Each aerosol was administered on a separate day and was inhaled through a mouthpiece during tidal breathing. Specific airway resistance (SRaw) was measured before and after the subjects inhaled aerosols delivered at as much as 5 doubling nebulizer outputs. For each aerosol challenge, an output-response curve was generated, and the nebulizer output required to increase SRaw by 100% above baseline (PO100) was calculated. Mean values of PO100 were significantly lower for each of the hypoosmolar acids than for hypoosmolar saline (1.65 + 0.43 g/min [mean + SEM] for saline compared with 0.95 + 0.11, 1.05 + 0.20, and 0.90 + 0.14 for H2SO4, HNO3, and a 1:1 mixture of the two; all p values less than 0.025). Mean values of PO100 did not differ among the 3 acids studied. For 7 of 12 subjects, all 3 acids caused a leftward shift in the output-response curve from the curve generated for hypoosmolar saline aerosol. Isoosmolar H2SO4 did not increase SRaw by 100% in any subjects, even at the maximal nebulizer output that delivered a concentration of H2SO4 in excess of 40 mg/m3.(ABSTRACT TRUNCATED AT 250 WORDS)
The development of cardiac catheterization at the University Hospital.
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Homograft aortic valve replacement 1971 - 1978.
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Effect of oral contraceptives on plasma clearance.
The effects of chronic steroid contraceptive therapy on drug clearance from plasma were studied by using plasma antipyrine, phenylbutazone, and cholecalciferol half-lives in women. After 3 mo of oral steroid therapy (Norinyl, 2 mg; norethindrone + mestranol), the antipyrine half-life was increased in 3 of 6 subjects, phenylbutazone half-life was not consistently altered, and vitamin D3 half-life was increased in 3 of 4 patients. After 1 to 7 yr of oral steroid theraphy, the antipyrine half-life was longer while taking the contraceptive than when the contraceptive treatment was discontinued in 4 of 6 subjects, whereas that of phenylbutazone was not consistently altered.