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Biomedical subjects

G M Turino

Publications and source records attributed to G M Turino.

At least 19 recordsLinked to original sources
PubMed2000

The effect of hyaluronan on elastic fiber injury in vitro and elastase-induced airspace enlargement in vivo.

This laboratory has previously described a method of preventing air-space enlargement in experimental pulmonary emphysema using aerosolized hyaluronan (HA). Although it was found that HA preferentially binds to elastic fibers (which undergo breakdown by elastases in emphysema), it remains to be shown that such attachment actually prevents damage to the fibers. In the current study, cell-free radiolabeled extracellular matrices, derived from rat pleural mesothelial cells, were used to test the ability of low molecular weight ( approximately 100 kDa) streptococcal HA to prevent elastolysis. Coating the matrices with HA significantly decreased elastolysis (P<0.05) induced by porcine pancreatic elastase (43%), human neutrophil elastase (53%), and human macrophage metalloelastase (80%). Concomitant in vivo studies examined the ability of an aerosol preparation of the streptococcal HA to prevent experimental emphysema induced by intratracheal administration of porcine pancreatic elastase. As seen with earlier studies involving bovine tracheal HA, a single aerosol exposure significantly decreased elastase-induced airspace enlargement, as measured by the mean linear intercept (107.5 vs 89.6 microm; P < 0. 05). Furthermore, repeated exposure to the HA aerosol for 1 month did not reveal any morphological changes in the lung. The results provide further evidence that aerosolized HA may be an effective means of preventing pulmonary emphysema and perhaps other lung diseases that involve elastic fiber injury.

Aerosols↗
PubMed2000

Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV(1) decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV(1) 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV(1) decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV(1) 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments.

Adult↗
PubMed1999

The pulmonary matrix, glycosaminoglycans and pulmonary emphysema.

This paper reviews recent evidence of the effect of intratracheal hyaluronan (HA) to limit the induction of experimental emphysema in hamsters. Experimental emphysema was induced by both neutrophil and pancreatic elastase instilled intratracheally. Emphysema was quantified anatomically by measurement of alveolar mean linear intercept. Hyaluronidase, instilled intratracheally, enhanced the induction of experimental emphysema. Air-space size measured one week after intratracheal instillation of elastase showed that administration of 1 mg HA immediately following elastase administration resulted in a marked reduction in air-space enlargement (82 microM vs 122 microM, p < 0.01). Similarly, animals given either 1 or 2 mg HA 2 h before elastase or 2mg HA 1 h after elastase showed a significant decrease in air-space enlargement compared to controls (96 microM, 88 microM vs 120 microM and 66 microM vs 104 microM, respectively; p < 0.05. Experimental emphysema induced by neutrophil elastase was also limited by the administration of 1 or 4 mg of HA, administered 2 h prior to elastase (57 and 59 microM, respectively vs 64 for controls, p < 0.05). Characterization of administered HA showed a mean molecular weight of 104,800 Da, less than 5% protein and a uronic acid/hexosamine ratio of 1, which is characteristic of HA. Studies using fluorescein-labeled hyaluronan (HA) showed fluorescence associated with interstitial, pleural and vascular elastic fibers. The mechanism of attachment of the administered HA to elastin remains unknown. Fluorescein labeling of elastin was visible for at least 4 h post-instillation. These studies indicate a protective effect of hyaluronan against elastase degradation of pulmonary elastin in vivo by both pancreatic and neutrophil elastases. The anatomical studies further suggest a mechanism of protective coating of hyaluronan which may limit access to pulmonary elastin from neutrophils and alveolar macrophages. Results also suggest that a reduction in pulmonary hyaluronan content increases the susceptibility of elastin to degradation by elastases. These studies provide evidence for an antielastase effect of hyaluronan which is not dependent upon enzyme inhibition but on anatomical protection of pulmonary elastin by other mechanisms.

Animals↗
PubMed1998

Aerosolized hyaluronic acid decreases alveolar injury induced by human neutrophil elastase.

This laboratory has previously shown that an intratracheally instilled solution of hyaluronic acid (HA) protects the lung from elastase-induced airspace enlargement. In those studies, fluorescein-labeled HA was found to bind preferentially to lung elastic fibers, suggesting a mechanism for the protective effect. The current investigation extends these findings by examining the capacity of an aerosol preparation of HA to similarly inhibit elastase-induced lung injury. Syrian hamsters were exposed to aerosolized bovine tracheal HA (0.1% solution in water) for either 25 or 50 min, then immediately instilled intratracheally with 80 units of human neutrophil elastase. One week later the lungs were examined for airspace enlargement, using the mean linear intercept method. Animals exposed to HA for 50 min showed a significant decrease in airspace enlargement compared to controls exposed to aerosolized water alone (68.2 microm vs 85.9 microm; P < 0.05). The 25-min exposure to the HA aerosol also reduced the mean linear intercept compared to controls (73.7 microm vs 85.9 microm), but this decrease was not statistically significant. With regard to possible inflammatory effects of HA, there was no difference in the percentage of lavaged neutrophils between HA-treated and control lungs at 24 hr (1.4% vs 1.8%, respectively). As with earlier experiments using intratracheally instilled HA, aerosolized fluorescein-labeled HA was found to bind to lung elastic fibers. These results suggest that aerosolized HA may prevent elastase-mediated injury in pulmonary emphysema.

Administration, Inhalation↗
PubMed1997

Atopy, asthma, and emphysema in patients with severe alpha-1-antitrypysin deficiency.

Bronchial asthma is characterized by episodic airway obstruction and associated with wheezing, a bronchodilator response, an elevation in total serum IgE, and atopy. To determine whether asthma is more common in subjects with severe alpha 1-antitrypsin deficiency (alpha 1-ATD) and airway obstruction, we compared 38 patients who had this condition (Group 1) with 22 control patients with chronic obstructive pulmonary disease (COPD) (Group 2) and with five subjects with alpha 1-ATD and normal spirometry (Group 3). Subjects were evaluated with a symptom questionnaire, pulmonary function testing, intradermal allergen testing, and serum IgE measurement. Self-reported wheezing was a common symptom in all patient groups, but attacks of wheezing with dyspnea were significantly more common in Group 1. Of those patients with airway obstruction, more than 50% showed a bronchodilator response whether suffering from alpha 1-ATD or not. Atopy was more common in Group 1 than in Group 2 (48% versus 27%). Mean serum IgE for all groups was similar but significantly greater in patients with atopy. We estimated the prevalence of asthma in the study groups on the basis of the criteria of attacks of wheezing, reversible airway obstruction, atopy, and that increased IgE. The proportion of patients with asthma in Group 1 was significantly greater than that in Group 2 (22% versus 5%, p < 0.05). Our study shows that with control for the degree of airway obstruction, asthma, as defined, is more common in patients with alpha 1-ATD than in those without it. We suggest that a lack of alpha 1-AT in airways increases the propensity to develop asthma.

Adult↗
PubMed1996

Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.

This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.

Adult↗
PubMed1994

Evidence that fibronectin-immunoglobulin complexes occur normally in plasma.

This study was done to ascertain whether complexes of plasma fibronectin (PFn) and immunoglobulins (Igs) are normally present in plasma. PFn preparations from plasmas of six random human donors were analyzed for IgG, IgM, and IgA by competitive ELISA procedures. To look for direct evidence of circulating complexes, two of the plasma samples were chromatographed on Sephacryl S-300. PFn prepared from a pool of three plasmas by cryoprecipitation was studied by crossed immunoelectrophoresis to detect PFn-Ig complexes. The Ig content of PFn ranged from 0.78% to 9.0% IgG; 0.25% to 4.9% IgM, and 0.15% to 0.71% IgA. The relative amounts were IgG > IgM > IgA in every sample, but the total Ig content of PFn varied with the plasma donor. The Sephacryl S-300 chromatogram of the plasma from which Ig-rich PFn was made showed distortion of the PFn peak by Ig peaks. PFn prepared by cryoprecipitation contained PFn-immunoglobulin complexes. Plasma from adult beagle dogs was used to prepare canine PFn. IgM was detected in canine PFn by SDS-Page and by double diffusion experiments against antiserum to canine IgM. By crossed immunoelectrophoresis, a PFn-IgM complex was detected in canine plasma. The cryoprecipitate recovered from a Sephacryl S-300 chromatogram of canine plasma contained equivalent amounts of IgM and PFn. These data suggest that complexes of Igs with PFn are normally present in plasma.

Animals↗
PubMed1991

Early changes in lung tissue hyaluronan (hyaluronic acid) and hyaluronidase in bleomycin-induced alveolitis in hamsters.

Intratracheal instillation of bleomycin in hamsters initiates a series of events that mimic human interstitial pulmonary fibrosis. Because glycosaminoglycans and particularly hyaluronan (hyaluronic acid, HA), may play an important role in the extracellular matrix response to early injury and subsequent fibrosis, this study was undertaken to define the early time course of changes in HA and hyaluronidase. Hamsters were given either 1 unit bleomycin sulfate in 0.2 ml saline or 0.2 ml saline (control), and randomly selected animals from both groups were killed at Days 3, 5, 6, 7, 9, and 17. Glycosaminoglycan fractions prepared from lung tissue of individual animals were analyzed for HA. The maximal HA content was reached 6 days after instillation of bleomycin and was 14.6-fold the normal value. The weight of injured lungs was 2.3-fold the control value. Thus, the increase in HA content was 30-fold. By Day 7 the HA content had dropped sharply. It then declined gradually to approximately double control values at Day 17. The specific activity of lysosomal hyaluronidase was the same in bleomycin-treated lungs and control lungs. Total units of the enzyme were increased in injured lungs, even at the time of maximal HA content, indicating active turnover of HA. The maximal HA content occurs prior to the rise in collagen and elastin biosynthesis. This observation in addition to the magnitude of the increase and its abrupt decline suggest that HA may be an important initiating factor for pathologic changes in lung extracellular matrix components.

Animals↗
PubMed1990

The effect of 60% oxygen on air-space enlargement and cross-linked elastin synthesis in hamsters with elastase-induced emphysema.

Hyperoxia is routinely administered to patients with severe emphysema. To gain insight into the possibly adverse effects of such treatment, hamsters were exposed to 60% oxygen for 5 days, beginning 48 h after induction of pulmonary emphysema by intratracheal instillment of pancreatic elastase. Control groups consisted of (1) animals instilled with elastase and exposed to room air, (2) animals instilled with saline and exposed to 60% oxygen, and (3) animals instilled with saline and exposed to room air. Cross-linked elastin content and synthesis in the lung were measured immediately following termination of hyperoxia, and the mean linear intercept was determined 4 wk later. Cytologic examination of bronchoalveolar lavage fluids was also performed. Statistical significance was determined by a two-way analysis of variance. Results indicate that exposure to 60% oxygen significantly affected (p less than 0.05) air-space size, causing a 51% increase among elastase-treated hamsters (124 versus 82 microns) but only a 4% increment among saline-treated animals (52 versus 50 microns). When compared to other groups, animals treated with both elastase and hyperoxia had a significantly greater (p less than 0.01) percentage of neutrophils (28%) in their lung lavage fluids immediately following exposure to 60% oxygen. Although total lung elastin content was not altered by hyperoxia at this time, labelling of elastin cross-links was significantly increased (p less than 0.05). These studies demonstrate that exposure to 60% oxygen enhances elastase-induced lung injury. They also raise the possibility that oxygen therapy may, under certain circumstances, accelerate the progression of human emphysema.

Animals↗