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Biomedical subjects

R H Ingram

Publications and source records attributed to R H Ingram.

At least 19 recordsLinked to original sources
PubMed1992

Relationship among mediators, inflammation, and volume history with antigen versus hyperpnea challenge in guinea pigs.

Paralyzed mechanically ventilated guinea pigs constricted to a similar degree by either isocapnic hyperpnea or antigen challenge display significantly different lung resistance (RL) volume history responses to a deep breath. We compared bronchoalveolar lavage (BAL) mediator profiles, BAL total protein concentrations, and tissue histopathology of antigen-constricted (AC), hyperpnea-constricted (HC), and control guinea pigs to determine whether patterns of volume history near peak constriction could be related to specific patterns of lung mediators, indices of microvascular leakage, or severity of tissue inflammation assessed pathologically. Methacholine constricted (MC) animals served as a second control group for assessing the effects of direct smooth-muscle contraction on indices of inflammation and volume history responses. Our results show that despite similar baseline and postchallenge RL, HC and MC animals displayed significant constriction reversal after a deep lung inflation, whereas AC animals did not. BAL concentrations of prostaglandin D2(PGD2), thromboxane B2 (TxB2), and leukotriene C4/D4/E4 (slow reacting substance of anaphylaxis, SRSA) were significantly elevated in both AC and HC animals compared with control and MC animals, with AC and HC BAL differing only with respect to PGD2 values (AC 2.4-fold higher). BAL total protein in AC animals was significantly greater than in HC, MC, and control animals. Histopathology showed significant peribronchial and interstitial cellular inflammation in AC animal specimens, whereas specimens from HC animals had little or no inflammation. Differences in volume history responses observed between equally constricted AC, HC, and MC animals may be due to differences in airway and/or parenchymal microvascular leak and cellular inflammation.

Airway Obstruction↗
PubMed1991

Asthma and airway hyperresponsiveness.

Airway hyperresponsiveness to a large number of stimuli is a characteristic of asthma in humans. Various components of the tracheobronchial tree might contribute to this characteristic, such as smooth muscle, the bronchial epithelium, various neurohumoral mechanisms, and the mechanical linkages between the lung parenchyma and the airways. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would ordinarily be well tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness.

Asthma↗
PubMed1991

Effects of capsaicin on mechanical, cellular, and mediator responses to antigen in sensitized guinea pigs.

To assess the role of tachykinins (TKs) in immediate hypersensitivity allergic reactions in guinea pigs (GPs), we compared airway mechanics and bronchoalveolar lavage (BAL) cell and inflammatory mediator profiles in three groups of GPs after ovalbumin aerosol challenge: (1) saline-sensitized, noncapsaicinized (control) (n = 9); (2) ovalbumin-sensitized, noncapsaicinized (OS) (n = 9); (3) ovalbumin-sensitized capsaicinized (OSC) (n = 9). Lung resistance (RL), dynamic elastance (EL), BAL cell counts, histamine, and eicosanoid mediator levels were measured at baseline on Day 1, and then on Day 14 after aerosolized antigen challenge. We found significant increases on Day 14 compared with Day 1 in the following: (1) postchallenge RL and EL in OS and OSC GPs, but not in control GPs; (2) BAL total cells and red cells in OS and OSC GPs; (3) BAL prostaglandin D2 (PGD2) thromboxane B2 (TxB2), sulfidopeptide leukotrienes (LTC4/D4/E4), and histamine in OS and OSC animals. Further, when data from all GPs were considered in distributed fashion, we noted positive linear correlations between peak postchallenge RL versus BAL concentrations of each of the following: PGD2, PGF2 alpha, TxB2, LTC4/D4/E4, leukotriene B4 (LTB4), and histamine. We found no significant differences in mediator or cellular responses between OS and OSC GPs. To verify that our method of capsaicinization resulted in TK depletion from the lungs of OSC GPs, substance P (SP) and neurokinin A (NKA) lung tissue levels were measured by ELISA in seven other animals, four treated with capsaicin using the same protocol and three treated with diluent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Nonhomogeneous lung emptying in cystic fibrosis patients. Volume history and bronchodilator effects.

In spontaneous asthma after a deep inhalation (DI) obstruction occurs in direct proportion to disease severity. Since this has been associated with peripheral inflammation, which is present in cystic fibrosis (CF), we tested whether worsening obstruction after DI also occurs in CF in 12 patients. We assessed volume history effects by comparing isovolumic expiratory flows (Vmax) during forced exhalation begun at the end of tidal inspiration (partial P) with those begun at TLC (maximal M) to obtain M/P. As in asthma there was a correlation between M/P and FEV1 (% predicted; r = 0.64, p less than or equal to 0.03, n = 12). To control for a time dependency effect due to preferential emptying of fast compartments early in both the P and M maneuvers, we compared Vmax obtained from a first partial (P1) with a second (P2) obtained after inspiration to TLC and slow exhalation to the same starting volume as P1 (P2/P1). In contrast to asthma the P2/P1 was greater than the M/P and not related to disease severity. A further index of nonhomogeneous lung emptying was the relationship between M/P and the slope ratio at 70% TLC (r = -0.67, p less than or equal to 0.03). After isoetharine inhalation the M/P decreased (-0.12 +/- 0.12, p less than or equal to 0.01) but no change was apparent in P2/P1, indicating further increases in the degree of nonhomogeneity. We conclude that although volume history effects on M/P are similar in asthma and CF, this is due to a predominance of parenchymal hysteresis in the former and nonhomogeneity in the latter, which worsens with bronchodilator use.

Bronchodilator Agents↗
PubMed1991

Interaction between parenchyma and airways in chronic obstructive pulmonary disease and in asthma.

The extent of air-space destruction caused by emphysema is very variable in severe chronic obstructive pulmonary disease (COPD), constituting one of the most obvious differences between COPD and asthma. Differences in the static deflation pressure-volume curve between COPD and asthma can easily be shown, but it has been surprisingly difficult to find distinctive mechanical features of impaired airway function caused by air-space destruction. This may be because in mild airway obstruction related to smoking--particularly in younger subjects--emphysema may be absent, and the predominant site of airway narrowing in the smallest bronchi and respiratory bronchioles may be the same as that found in asthma in remission. In more severe obstruction caused by COPD there is almost always very severe intrinsic disease of the airways and this may so dominate the functional abnormality that it is difficult to detect any additional change because of airspace destruction. Overall, few studies have set out to detect specific effects of parenchymal destruction on airway function.

Airway Resistance↗
PubMed1990

Breathing pattern affects respiratory heat loss but not bronchoconstrictor response in asthma.

To determine whether changes in breathing pattern alone affect respiratory heat loss (RHL) and the constrictor response to cold dry gas hyperpnea in asthmatic subjects, we performed the following 2 part study: first we measured RHL in 8 asthmatic and 8 normal subjects during controlled eucapnic hyperpnea while they breathed at inspiratory to expiratory ratios (I/E) of 1:3, 3:1, and 2:2, and we recorded postchallenge forced expiratory volume in 1 sec (FEV1) in the asthmatic group; we then performed the same measurements in 8 asthmatic and 8 normal subjects at fixed target minute ventilation (VE) for tidal volumes of 0.2 X Forced vital capacity (FVC), 0.4 X FVC, and 0.6 X FVC by varying the target respiratory rate appropriately. Our results show that (1) increasing I/E ratio or tidal volume-frequency ratio (VT/f) at fixed VE produced small but statistically significant increases (p less than 0.05) in overall heat loss per unit volume of respired gas (RHL/VE) in both asthmatic and nonasthmatic subjects of 1-4 cal/L; (2) changes in breathing pattern alone did not affect bronchoconstrictor response as assessed by lack of change in slopes and intercepts of % delta FEV1 vs. RHL dose-response curves; and (3) the increase in RHL per unit volume of respired gas resulting from increasing VT/f ratios during cold gas hyperpnea was significantly greater in asthmatic than in nonasthmatic subjects. We conclude that changes in breathing pattern may affect overall RHL measured at the mouth, although the maximum effect of such changes in both asthmatic and nonasthmatic subjects is small (10-15%); that such changes do not significantly alter airway constrictor response in asthmatic persons; and (3) that the effects of changing breathing pattern on RHL may be more pronounced in asthmatic than nonasthmatic subjects, which suggests that the asthmatic group may be less able to adapt to factors that alter the magnitude and site of RHL.

Adult↗
PubMed1990

Physiological assessment of inflammation in the peripheral lung of asthmatic patients.

Even the asymptomatic asthmatic person with normal lung function may have peripheral airway obstruction and inflammation along with hyperresponsiveness to nonspecific challenges. The airway caliber change induced immediately following a deep inhalation (DI) appears to relate to the mechanism (inflammation vs. smooth muscle constriction) and site (peripheral vs. more central) of obstruction and the degree of hyperresponsiveness. Data are presented and reviewed that support the notion that relative hysteresis of parenchyma (including peripheral airways and alveolar ducts) and airways (more centrally located, conducting airways) can explain the magnitude and sign of airway caliber change that follow a DI in asthmatic subjects.

Airway Obstruction↗
PubMed1990

Effects of increasing doses of beta-agonists on airway and parenchymal hysteresis.

We examined the effects of a deep inhalation on airway caliber before and after increasing doses of a beta-agonist in eight subjects, including one former and two current but mild asthmatics. With bronchodilation the increase in maximal flow on the partial flow-volume curve (P), initiated from functional residual capacity, exceeded that seen on the maximal curve (M), initiated from total lung capacity, such that isovolumic maximal flows diminished after a deep inhalation; i.e., M/P ratios fell with bronchodilation, as we and others have found. Five of eight reversed this downward trend in M/P ratios at higher cumulative doses. Quasistatic pressure-volume curves (QSPV) were simultaneously performed on two of these five and demonstrated a decrease in pressure-volume hysteresis (PVH) at the higher doses associated with a rising M/P ratio. Three of eight had continuing low and diminishing M/P ratio up to the highest dose given. QSPV were performed in two of these three and indicated no change in PVH at any of the doses. One of these two had a repeat study using a subcutaneous beta-agonist after the inhaled drug was given, and the M/P ratio rose as QSPV PVH fell. These data support the relative hysteresis analysis of airway and parenchyma as an explanation for volume history effects on airway caliber.

Administration, Inhalation↗
PubMed1990

Bronchoalveolar lavage cell and mediator responses to hyperpnea-induced bronchoconstriction in the guinea pig.

We studied the association between bronchoconstriction and bronchoalveolar lavage (BAL) cell and mediator profiles in unsensitized guinea pigs (GP) after hyperpnea to determine whether eicosanoids or histamine are released during hyperpnea-induced bronchoconstriction (HIB). Twelve animals were challenged with warm, moist (WM) air (T = 35 degrees C, relative humidity = 91 to 94%), 14 with room dry (RD) air (T = 25 degrees C, relative humidity less than 2.1%), and 18 with cold, dry (CD) air (T = 7 degrees C, relative humidity less than 2.1%). Lung resistance (RL) and elastance (EL) were recorded at baseline and at 2-min intervals after hyperventilation. Challenges were terminated either when a greater than or equal to 100% increase in RL was observed postchallenge or after completion of a 135 breaths/min challenge if RL did not increase. BAL was performed, and samples were analyzed for total cells, white cell and epithelial cell differentials, total protein concentration, and mediator content.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1990

Assessment of bronchoalveolar cell and mediator response to isocapnic hyperpnea in asthma.

The purpose of this study was to test the hypothesis that mediators and cells associated with bronchoconstriction or inflammation are locally synthesized and/or released in the airways of asthmatic subjects in response to isocapnic hyperpnea (ISH). Seven atopic, mildly asthmatic subjects were studied. Baseline measurements were reported previously and included forced expiratory volumes, flow rates, bronchoalveolar lavage (BAL), and methacholine reactivity. Approximately 1 yr later, spirometry and BAL were repeated, but BAL was performed immediately after ISH challenge. As indices of inflammation, BAL measurements were made of eosinophils, neutrophils, epithelial cells, leukotrienes B4, C4, D4, and E4, prostaglandins D2, E2, and F2 alpha, thromboxane B2, histamine, and total protein. Compared with baseline, ISH was associated with higher BAL concentrations of the following: leukotriene B4 (10 versus 121 pg/ml, p = 0.02), leukotrienes C4/D4/E4 (46 versus 251 pg/ml, p = 0.02), eosinophils (0.8 versus 2.2%, p = 0.04), and epithelial cells (2.1 versus 6.1%, p = 0.05). Trends toward significant increases were seen in BAL concentrations of neutrophils and prostaglandin D2. No statistically significant increases were found in BAL measurements of total protein, histamine, prostaglandins E2 or F2 alpha, thromboxane B2, lymphocytes, or macrophages. The magnitude of the response to ISH, as measured by change in FEV1, did not correlate with BAL levels of cells or mediators. This study indicates that ISH, even in mildly asthmatic subjects, is associated with airway increases in a spectrum of bronchoactive mediators and inflammatory cells, supporting the observations of others that antagonists of a single mediator are unlikely to have major clinical effectiveness in ISH or exercise-induced asthma.

Adult↗
PubMed1989

Effects of lung volume, volume history, and methacholine on lung tissue viscance.

We examined the effects of lung volume change and volume history on lung resistance (RL) and its components before and during induced constriction. Eleven subjects, including three current and four former asthmatics, were studied. RL, airway resistance (Raw), and, by subtraction, tissue viscance (Vtis) were measured at different lung volumes before and after a deep inhalation and were repeated after methacholine (MCh) aerosols up to maximal levels of constriction. Vtis, which average 9% of RL at base line, was unchanged by MCh and was not changed after deep inhalation but increased directly with lung volume. MCh aerosols induced constriction by increasing Raw, which was reversed by deep inhalation in inverse proportion to responsiveness. such that the more responsive subjects reversed less after a deep breath. Responsiveness correlated directly with the degree of maximal constriction, as more responsive subjects constricted to a greater degree. These results indicate that in humans Vtis comprises a small fraction of overall RL, which is clearly volume-dependent but unchanged by MCh-induced constriction and unrelated to the degree of responsiveness of the subject.

Adult↗
PubMed1989

Responsiveness, inflammation, and effects of deep breaths on obstruction in mild asthma.

Using cellular and biochemical characteristics of bronchoalveolar lavage (BAL) liquid as an index of inflammation, we examined the relationships between change of airway caliber after a deep inhalation (DI), degree of base-line airway hyperresponsiveness, and peripheral airway inflammation in a group of 16 atopic asymptomatic mild asthmatics and 6 normal subjects. Compared with normal subjects, asthmatics demonstrated 1) significantly higher BAL concentrations of histamine, total protein, the sulfidopeptide leukotrienes (SRS-A), and leukotiene B4; 2) a decrease in specific airway conductance (sGaw) with a DI at base line vs. an increase in normal subjects (before vs. after percent change in sGaw, -10 vs. 12, P less than 0.05); and 3) no significant difference in BAL total cell count or leukocyte differential. Significant correlations were demonstrated between 1) percent of BAL eosinophils vs. degree of airway hyperresponsiveness; 2) base-line level of airway obstruction vs. degree of hyperresponsiveness; 3) effects of a DI vs. BAL concentrations of eosinophils, total protein, and histamine; 4) base-line forced expired volume in 1 s vs. BAL concentrations of total protein and histamine; and 5) BAL concentrations of the various mediators with each other. These data support the notion that 1) the response to a DI in mild, stable asthmatics represents a physiological indicator of peripheral obstruction because of inflammation and 2) this inflammation is associated with increases in several known mediators of airway inflammation and hyperreactivity.

Adult↗
PubMed1989

Localization of the site of the bronchoconstrictor effects of leukotriene C4 compared with that of histamine in asthmatic subjects.

Although the sulfidopeptide leukotrienes are known to be potent bronchoconstrictors, the relative aerodynamic site of response to these compounds is controversial. We determined the decrease in maximal expiratory flow rates (Vmax) from partial and maximal flow-volume curves in seven asthmatic subjects after inhalation of aerosols of histamine or leukotriene C4 (LTC4) while breathing air or a mixture of 80% helium and 20% oxygen (He/O2). Density dependence (DD) of maximal expiratory flow was determined from partial expiratory flow volume curves by an isovolumic comparison of maximal expiratory flows with subjects breathing He/O2 with those obtained while breathing air. Measurements were made before and after inhalation of aerosols generated from graded concentrations of each constrictor agent. An aerodynamic site of response to LTC4 more central than for histamine was indicated by a significant (p less than 0.02) increase in DD with the former but not with the latter agonist. The ratio of Vmax at 30% vital capacity determined from maximal and partial maneuvers (M/P) was routinely higher at baseline while breathing He/O2 compared to the corresponding values with air, suggesting a degree of peripheral obstruction that was reversed by a deep inhalation. Obstruction induced by LTC4 inhalation resulted in a greater increase in M/P compared with baseline when air was the test gas (p less than 0.02). This was not observed when He/O2 was the test gas. Similar effects on M/P were not induced by histamine aerosol inhalation, consistent with a central airway response to LTC4 that was not affected by volume history.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1989

The effects of deep inhalation on maximal expiratory flow during intensive treatment of spontaneous asthmatic episodes.

Asthmatic patients who came to hospital for treatment of severe attacks were assessed for level of obstruction and the effects of a deep inhalation (DI) on degree of obstruction at various stages of their treatment and after recovery over several days. The more severe the obstruction, the greater was the constrictor effect of a DI; as lung function improved with intensive treatment, including corticosteroids, the constrictor effect diminished. Thus, we believe the constrictor effects of a DI relate to the degree of inflammation in the obstructive process. These longitudinal data relating severity to the effects of a DI were nearly identical to previously published cross-sectional data in a group of patients with spontaneous asthma with widely different levels of lung function. It is possible that the response to a DI in a given asthmatic subject serves as a functional marker for the predominant mechanism for obstruction.

Adult↗
PubMed1988

Lung inflation does not increase maximal expiratory flow during induced obstruction in the dog.

A deep inflation (DI) reverses induced bronchoconstriction in normal human subjects whether assessed by airway resistance before and after a DI or by isovolumic maximal expiratory flows (Vmax) from partial expiratory flow-volume (PEFV) vs. maximum expiratory flow-volume (MEFV) maneuvers. These observations suggest that with induced constriction the hysteresis of airways exceeds that of the parenchyma. In contrast with humans, a previous study of ours on dogs indicated that induced increases in airway resistance were unaffected by DI, suggesting that hysteresis of airways and parenchyma were equal. We hypothesized therefore that in constricted dog lungs, any differences that might arise in isovolumic Vmax between PEFV and MEFV maneuvers would not be due to changes in airway caliber but rather would be wholly determined by isovolumic differences in deflational recoil pressures. Recoil pressures were dynamically measured using six separate alveolar capsules in each of six dogs. At base line there were no significant differences between isovolumic recoil pressures or maximal flows with volume history, suggesting equal degrees of airway and parenchymal hysteresis. After histamine-induced constriction there were also no isovolumic differences in flows, but due to striking nonhomogeneities in dynamic recoil pressure among alveolar capsules, it was not possible to express a single meaningful recoil pressure pertinent to the lungs as a whole. These findings are consistent with the idea that isovolumic comparisons of Vmax serve as a reasonable indicator of changes in the relative degree of airway and parenchymal hysteresis.

Airway Obstruction↗
PubMed1988

Methacholine-induced bronchoconstriction in dogs: effects of lung volume and O3 exposure.

The maximal effect induced by methacholine (MCh) aerosols on pulmonary resistance (RL), and the effects of altering lung volume and O3 exposure on these induced changes in RL, was studied in five anesthetized and paralyzed dogs. RL was measured at functional residual capacity (FRC), and lung volumes above and below FRC, after exposure to MCh aerosols generated from solutions of 0.1-300 mg MCh/ml. The relative site of response was examined by magnifying parenchymal [RL with large tidal volume (VT) at fast frequency (RLLS)] or airway effects [RL with small VT at fast frequency (RLSF)]. Measurements were performed on dogs before and after 2 h of exposure to 3 ppm O3. MCh concentration-response curves for both RLLS and RLSF were sigmoid shaped. Alterations in mean lung volume did not alter RLLS; however, RLSF was larger below FRC than at higher lung volumes. Although O3 exposure resulted in small leftward shifts of the concentration-response curve for RLLS, the airway dominated index of RL (RLSF) was not altered by O3 exposure, nor was the maximal response using either index of RL. These data suggest O3 exposure does not affect MCh responses in conducting airways; rather, it affects responses of peripheral contractile elements to MCh, without changing their maximal response.

Airway Resistance↗