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PubMed2004

Mechanics, nonlinearity, and failure strength of lung tissue in a mouse model of emphysema: possible role of collagen remodeling.

Enlargement of the respiratory air spaces is associated with the breakdown and reorganization of the connective tissue fiber network during the development of pulmonary emphysema. In this study, a mouse (C57BL/6) model of emphysema was developed by direct instillation of 1.2 IU of porcine pancreatic elastase (PPE) and compared with control mice treated with saline. The PPE treatment caused 95% alveolar enlargement (P = 0.001) associated with a 29% lower elastance along the quasi-static pressure-volume curves (P < 0.001). Respiratory mechanics were measured at several positive end-expiratory pressures in the closed-chest condition. The dynamic tissue elastance was 19% lower (P < 0.001), hysteresivity was 9% higher (P < 0.05), and harmonic distortion, a measure of collagen-related dynamic nonlinearity, was 33% higher in the PPE-treated group (P < 0.001). Whole lung hydroxyproline content, which represents the total collagen content, was 48% higher (P < 0.01), and alpha-elastin content was 13% lower (P = 0.16) in the PPE-treated group. There was no significant difference in airway resistance (P = 0.7). The failure stress at which isolated parenchymal tissues break during stretching was 40% lower in the PPE-treated mice (P = 0.002). These findings suggest that, after elastolytic injury, abnormal collagen remodeling may play a significant role in all aspects of lung functional changes and mechanical forces, leading to progressive emphysema.

Animals↗
PubMed2006

Pulmonary emphysema: when more is less.

Pulmonary emphysema results from the loss of intricate alveolar architecture and progressive simplification of small and highly effective gas-exchanging units into large, inefficient cyst-like spaces. Because of the loss of alveolar gas-exchanging units and the capillary bed within them, blood oxygen levels eventually fall and pressures within the pulmonary circulation rise. Recent insights from genetically manipulated mouse models have refined our understanding of the molecular events that prevent or promote the development of pulmonary emphysema. Capitalizing on an improved molecular understanding of emphysema with improved therapeutics has the potential to enhance both the survival and quality of life of patients with this common lung disease.

Animals↗
PubMedDate not supplied

Protease inhibitor phenotype BsaskatoonM is not associated with emphysema - a 20-year follow-up study.

OBJECTIVE: To investigate the association between the PiBsaskatoon variant of alpha-1 protease inhibitor (a1 Pi), present in the heterozygous state, and the development of emphysema. DESIGN: Twenty-year follow-up in the third generation of a family with the variant, naturally controlled with regard to both environmental influences and other genetic factors. SETTING: University teaching hospital. POPULATION STUDIED: Ten siblings, five with PiBsaskatoonM phenotype and five with PiM phenotype, 33 to 46 years of age. INTERVENTIONS: Respiratory symptoms and smoking histories; pulmonary function tests, including static lung volumes, dynamic lung volumes before and after salbutamol 200 mg, and diffusing capacity; allergen prick skin tests; serum a1 Pi level, chest radiographs and high resolution computerized tomography lung scans MAIN RESULTS: The two groups of siblings had similar mean ages, smoking histories and prevalence of current mild respiratory symptoms. Pulmonary function data showed normal mean values and no statistically significant differences for all the variables between the two groups. Chest radiographs were normal in all subjects. High resolution computerized tomography scans were normal in eight subjects, and demonstrated mild and very mild centrilobular emphysema in the two subjects with greatest smoking histories (approximately 30 pack-year each); both of these were PiBsaskatoonM phenotype. CONCLUSION: There is no evidence of an association between a1 Pi phenotype PiBsaskatoonM and the development of emphysema.

Adult↗
PubMed1999

Massive pulmonary hemorrhage due to cytomegalovirus infection in a Japanese patient with alpha-1-antitrypsin-deficient emphysema.

Although alpha(1)-antitrypsin (AAT) deficiency is one of the most common hereditary diseases and a recognized cause of emphysema in Caucasians, variants of this deficiency are extremely rare among Orientals. We present here a Japanese emphysema patient with the AAT deficiency variant originally identified as S(iiyama). After an 8-year follow-up period, the patient suffered from repeated pulmonary Pseudomonas aeruginosa infection for 4 years. He died suddenly of massive pulmonary hemorrhage. The pathologic examination revealed a necrotic hematoma in the right S10 lobe, which exhibited pneumonia due to cytomegalovirus (CMV) infection. Pulmonary hemorrhage due to CMV can occur and be fatal in patients with emphysema and AAT deficiency.

Adult↗
PubMed2000

Effects of hemoglobin on pulmonary arterial pressure and pulmonary vascular resistance in patients with chronic emphysema.

BACKGROUND: The increase in viscosity caused by secondary polycythemia is thought to be one of the major causes of pulmonary hypertension secondary to chronic emphysema. However, very few clinical studies considered the relation between pulmonary hypertension and polycythemia in the case of chronic obstructive pulmonary disease. OBJECTIVE: The purpose of this study is to elucidate the relative contribution of an increase in hemoglobin level (Hb) to mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). METHODS: We retrospectively investigated 41 patients with chronic emphysema who had undergone a right heart catheterization. Multiple-regression analysis and F test were performed to investigate both direct effects of Hb and PaO(2) as independent variables on mPAP and PVR as dependent variables. RESULTS: Significant correlations were found between PaO(2) and mPAP (or PVR), or Hb and mPAP (or PVR), indicating that both Hb and PaO(2) are contributory to mPAP and PVR. The F test demonstrated that Hb and PaO(2) could directly affect the level of either mPAP or PVR. CONCLUSIONS: It was concluded that Hb had a direct effect on mPAP and PVR, independently of hypoxia in patients with chronic emphysema.

Aged↗
PubMedDate not supplied

Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema.

BACKGROUND: Administration of ALL-TRANS retinoic acid (ATRA) to adult Sprague-Dawley rats with emphysema induced by porcine pancreatic elastase (PPE) reversed the emphysema perhaps by inducing new alveolar formation. OBJECTIVE: A study was conducted to determine whether ATRA can induce new alveolar septa and reverse the airspace enlargement caused in adult mice by PPE treatment. METHODS: 48 FVB mice were divided into 6 groups. Three groups received 15 microg of PPE in 0.1 ml of 0.9% saline and 3 groups received 0.1 ml of saline, intratracheally. Starting at day 22, the mice received 12 daily intraperitoneal injections of cottonseed oil, with or without ATRA (12.5 microg or 50 microg). The mice were killed for study 1 day after the last injection. RESULTS: Measurements of plasma and lung tissue ATRA levels showed statistically significant elevated levels after the 50-microg but not after the 12.5-microg doses of ATRA. In situ hybridization studies of elastin and alpha(1)(I) collagen mRNA expression in pulmonary parenchyma as well as in airways and blood vessels showed no effect of ATRA. Airspace size was determined by the mean linear intercept (Lm) method. The Lm of the groups receiving PPE and ATRA (46.2 +/- 4.1 microm, mean +/- SD) was not significantly different from the group receiving PPE and oil (47.8 +/- 6.0 microm). The Lm for groups receiving saline and ATRA (40.6 +/- 2.5 microm) were not significantly different from the group receiving saline and oil (41.0 +/- 2.7 microm). Comparison of the fixed lung volume data and calculated internal surface area also showed no differences between the control and ATRA-treated groups. CONCLUSION: ATRA treatment does not affect airspace size or expression of elastin or alpha(1)(I) collagen mRNA in adult FVB mice with PPE-induced emphysema.

Animals↗
PubMed1986

Changes of volume of trapped gas after bronchodilation in subjects with suspected subclinical emphysema.

We studied the volume of trapped gas (VTG), using a nitrogen washout method, before and after bronchodilation in four groups with theoretically increasing risk of developing pulmonary emphysema: (1) nonsmoking healthy controls (PiMn), (2) nonsmoking subjects with an intermediate alpha 1-antitrypsin deficiency (PiMZn), (3) smoking subjects with normal concentration of alpha 1-antitrypsin, and (4) smoking PiMZ subjects. VTG was the only lung function variable that showed a significant difference between PiMZn and PiMn subjects but only after bronchodilation. Some conventional lung function tests also distinguished smokers from nonsmokers of both genotypes but VTG was the most sensitive test. VTG decreased after salbutamol inhalation in the control group but showed a consecutively larger increase with more risk factors of developing emphysema. An increase in VTG after bronchodilation may be a sign of alveolar abnormality preceding development of clinical lung emphysema.

Albuterol↗
PubMed1996

Clinical significance of serum concentration of interleukin 8 in patients with bronchial asthma or chronic pulmonary emphysema.

Interleukin-8 (IL-8) belongs to the family of chemotactic cytokines and has been shown to activate neutrophils in vitro and in vivo. In this study, we measured IL-8 concentration in the serum of patients with pulmonary emphysema or bronchial asthma. IL-8 concentration in serum of emphysema patients was significantly higher than in asthmatics; in emphysema patients it was significantly correlated with the smoking index and the annual decrease of FEV1.0. In asthmatics IL-8 concentration was below the level of detection, but was markedly increased during exacerbation of asthma. Our findings suggest that IL-8 may be one of the causal factors in these diseases.

Adolescent↗
PubMed1996

Protection of rat lung from elastase-induced elastic fiber degradation in vitro and from emphysema in vivo by a trifluoroacetylpeptide anilide inhibitor.

Trifluoroacetylpeptide anilides are powerful reversible inhibitors of human neutrophil elastase (HNE), a serine protease implicated in the pathogenesis of pulmonary emphysema. The in vitro effectiveness of three inhibitors, CF3CO-Phe-Ala-NH-p-C6H4-CF3 (1), CF3CO-Val-Ala-NH-p-C6H4-CF3 (2) and CF3CO-Lys-Ala-NH-p-C6H4-CH(CH3)2 (3) was analyzed. The protection of lung tissue sections of rats from the degradation induced by HNE has been evaluated quantitatively by automated image analysis. Inhibitor 1 (22 microM), 2 (50 microM) or 3 (35 and 70 microM) significantly reduced the HNE-induced degradation of the elastin network by 75, 42, 54 and 44%, respectively. Inhibitor 3 was tested intratracheally on an experimental model of pulmonary emphysema. Rats that received the elastase inhibitor 1 h before instillation of HNE were significantly protected by 40% from experimental emphysema. Reduced protections were observed with the treatment by the inhibitor 1 or 4 h after challenge with the enzyme.

Anilides↗
PubMed1996

Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ).

Alpha 1-Antitrypsin deficiency predisposes to pulmonary emphysema, liver cirrhosis and hepatocellular carcinoma. Anecdotal evidence and a large autopsy study suggest that severe lung and liver disease rarely coexist in the same subject, but this has not been studied in patients. Therefore we investigated 27 patients with severe alpha 1-deficiency (Pi ZZ) and pulmonary emphysema for signs of liver disease and impaired hepatic function. A subgroup of 7 patients underwent quantitative liver function tests. On physical examination or ultrasonography, cirrhosis or tumor was not suspected in any patient. Conventional liver function tests were completely normal in 17 patients. Elevated serum activities of gamma-glutamyltranspeptidase and/or aminotransferases were seen in 10 patients. In some, the elevation was only marginal and in none more than twice normal. The serum bilirubin concentration and activity of alkaline phosphatase were increased in 1 patient. Serum protein, albumin, fibrinogen, antithrombin III, alpha 1-fetoprotein concentrations, serum activities of cholinesterase and glutamate dehydrogenase, activated partial thromboplastin time and prothrombin time were normal in all patients. The indocyanine green half-life was abnormal only in 1 of 6 patients, suggesting that hepatic blood flow was not impaired in the study group. However, the lidocaine half-life and galactose elimination capacity, parameters of hepatic metabolization, were impaired in 4 and 6 of 7 patients, respectively. We conclude that liver disease or impaired liver function is not a clinically relevant problem in most patients with pulmonary emphysema due to alpha 1-antitrypsin deficiency. But results of quantitative liver function tests, although performed in only a small group of patients, suggest that hepatic metabolization might be impaired even in those patients who present with pulmonary disease.

Adult↗
PubMed2005

Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats.

BACKGROUND: Hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after lung injury. The goal of the present study was to characterize its role in pulmonary emphysema, which may lead to the development of new treatment strategies with HGF. METHODS AND RESULTS: HGF mRNA and protein levels in lung tissue and plasma from elastase-induced emphysema rats transiently increased, then declined significantly to below the basal level in a time-dependent manner (P<0.01). Furthermore, changes in HGF were correlated with histologically progressive emphysematous changes and deterioration in pulmonary physiology. Use of the HVJ (hemagglutinating virus of Japan) envelope method resulted in successful transfection of cDNA encoding human HGF, as demonstrated by an efficient expression of HGF in alveolar endothelial and epithelial cells. Transfection of HGF resulted in a more extensive pulmonary vasculature and inhibition of alveolar wall cell apoptosis, and those effects led to improved exercise tolerance and gas exchange (P<0.05), which persisted for more than 1 month. CONCLUSIONS: Decreased HGF expression due to a failure in sustained endogenous production after injury was associated with emphysema-related histopathologic and physiological changes in the present rat model. In addition, induction of HGF expression by a gene-transfection method resulted in improved pulmonary function via inhibition of alveolar cell apoptosis, enhancement of alveolar regeneration, and promotion of angiogenesis.

Animals↗
PubMed1994

The comparative effects of elastase-induced emphysema on costal and crural diaphragm and parasternal intercostal muscle contractility.

Chronically, hyperinflated human subjects with chronic obstructive pulmonary disease and animals with experimentally induced emphysema generate greater than expected levels of transdiaphragmatic pressure at high lung volume because of adaptive changes in the length-tension relationship of the costal diaphragm. The ability to lower intrathoracic pressure during inspiration depends on the mechanical action of all the inspiratory muscles acting in concert. However, the effect of chronic hyperinflation on the mechanical action of inspiratory muscles other than the costal diaphragm remains unknown. This study compares the effect of chronic hyperinflation in the form of elastase-induced emphysema on the contractile properties of the three major inspiratory muscles of the hamster (i.e., the costal and crural diaphragm and parasternal intercostals). Muscles were studied in vitro 6 months after emphysema was induced by intratracheal injection of elastase. Saline-injected animals served as controls. TLC in the elastase-injected hamsters was significantly greater than in controls (12.5 +/- 0.8 ml versus 9.0 +/- 0.3 ml, p < 0.002). Maximal tetanic tension, time to peak tension, maximal velocity of shortening, and the force-velocity relationship differed among the three muscles but for any given muscle were similar in control and emphysematous animals. In contrast, the fiber length optimal for tension generation (Lo) not only differed across muscles but was significantly shorter in the costal diaphragm of emphysematous animals compared with control animals. However, Lo of the parasternal intercostal and crural diaphragm was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1994

Neutrophil sequestration in lungs removed at surgery. The effect of microscopic emphysema.

Neutrophils within the lungs are considered to play an important role in the pathogenesis of pulmonary emphysema. We have studied the intravascular distribution of reinjected autologous 111In-labeled neutrophils in lung specimens resected 10 min after reinjection from 10 patients undergoing surgery for peripheral bronchogenic tumors. An excess of neutrophils relative to that expected for the 99mTc-labeled erythrocyte blood volume was confirmed in all specimens (range, 3- to 136-fold). In seven specimens which were completely examined, this excess displayed a skewed distribution, with a median neutrophil sequestration of 20-fold excess, and correlated with local blood volume (r = -0.51; p < 0.001). There was also a significant correlation between alveolar wall surface area per unit volume of lung (AWUV) and neutrophil excess, when randomly selected tissue blocks from each specimen were analyzed (r = 0.34, n = 51, p = 0.012). This same trend was demonstrated when whole specimen median values were considered (r = 0.64, n = 7, p = 0.07). Thus in areas of the lungs with lower AWUV values (increasing microscopic emphysema), fewer neutrophils were present. These studies add further support to the view that emphysema per se is not associated with an increased sequestration of pulmonary intravascular neutrophils.

Aged↗
PubMed1994

Expiratory flow pattern following single-lung transplantation in emphysema.

In single lung transplantation (SLT) recipients, a "plateau" of the maximal expiratory flow volume curve (MEFV) and a "biphasic" MEFV have been reported to reflect anastomosis pathology. A plateau is defined as constant airflow over a large expired volume early in the MEFV. A biphasic MEFV has an initial period of high flow followed by a terminal low flow phase. Models of expiratory flow limitation by wave speed, however, predict that the MEFV of SLT recipients with emphysema should both be biphasic and demonstrate a plateau even without anastomosis pathology. Review of the spirometries and clinical courses of our first ten patients receiving SLT for emphysema demonstrated a biphasic MEFV, and a plateau of the MEFV in all patients. No patient showed evidence of anastomosis pathology. Independent lung spirometries, generated by a novel technique, revealed that the initial high flow phase of the MEFV came from the transplanted lung and the terminal low flow from the native emphysematous lung. The location of the flow limitation was demonstrated to be immediately downstream from the anastomosis. Therefore, the MEFV of SLT recipients with emphysema routinely demonstrates both a biphasic pattern and a plateau, neither of which necessarily reflect anastomosis pathology.

Bronchoscopy↗
PubMed1995

Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness.

Based on our previous finding, of increased small airways disease in centrilobular emphysema (CLE) when compared with panlobular emphysema (PLE), we hypothesized that smokers who develop CLE would have increased airway responsiveness associated with airway inflammation and exaggerated airway narrowing, but not smokers with PLE. We compared preoperative methacholine challenge with the morphologic and cellular inflammatory characteristics of the airways in the lungs of six nonsmokers, 10 smokers with CLE, and five smokers with PLE. The airways of the CLE group were narrower than those of the nonsmokers (KS < 0.05) and the PLE group (KS < 0.05), but perimeters were not different. A greater percentage of airways in the CLE group showed infolding of the epithelium and lumen deformity than in the PLE group and nonsmokers (p < 0.05). Airway inner wall thickening (WI) was increased in the CLE group when compared with the PLE group and nonsmokers (p < 0.05), and WI correlated significantly with PC20 in the CLE group (r = -0.64, p < 0.01) but not in the PLE group and nonsmokers. The number of T lymphocytes in the airway walls correlated with PC20 in the CLE group (r = -0.50, p < 0.05) but not in the PLE group. In conclusion, despite similar age, smoking history, and range of airflow limitation, there was a clear difference in the methacholine responsiveness between the emphysema groups, suggesting that responsiveness is not just a reaction to smoking but either a reaction developing in some smokers or an abnormality initially present in some smokers which, in combination with exposure to cigarettes, determines the development of a type of lung disease: CLE.

Aged↗
PubMed1995

Alveolar inflammation and its relation to emphysema in smokers.

The prevalent theory in the pathogenesis of emphysema proposes that increased numbers of activated neutrophils and/or alveolar macrophages produce large amounts of proteases, an activity that cannot be regulated by alpha 1-antiproteases, resulting in lung destruction. However, the cells in the lung parenchyma of smokers have not been properly identified. We characterized and quantitated the inflammatory cell load in the lungs of smokers and correlated these findings with the degree of lung destruction. Twenty-one patients, six nonsmokers and 15 smokers, undergoing lung resection were studied. Lungs or lobes were fixed and stained for light microscopy and neutrophil identification and immunohistochemically stained for identification of lymphocytes and macrophages. By point counting, we determined the extent of emphysema by the volume density of the lung parenchyma (Vvalv), and the different cell numbers per cubic millimeter in all lungs. In nonsmokers Vvalv was greater than in smokers. The number of neutrophils/mm3 of lung correlated directly with the Vvalv, (r = 0.71, p < 0.01), whereas the number of alveolar macrophages (r = -0.70) and T-lymphocytes (r = -0.78) correlated negatively with the Vvalv. The number of T-lymphocytes correlated negatively with the number of neutrophils (r = -0.58) and positively with the numbers of alveolar macrophages (r = 0.77). Our data suggest that as long as the inflammatory reaction is predominantly of neutrophils there is no destruction of the lung. However, the extent of lung destruction becomes evident, and its extent is directly related to the number of alveolar macrophages and T-lymphocytes/mm3. We conclude that the T-lymphocyte might be importantly implicated in the pathogenesis of emphysema in smokers.

Adult↗
PubMed1996

Morphologic aspects of airways of patients with pulmonary emphysema followed by bronchial asthma-like attack.

Morphometric analysis of airways was performed in autopsied lungs from four patients with pulmonary emphysema (PE) followed by bronchial-asthma (BA)-like attacks (Group PE+BA) (four males, 72 +/- 9 yr). The results were compared with those from five pulmonary emphysema patients (Group PE) (five males, age 71 +/- 4 hr), three patients with bronchial asthma (Group BA) (one female and two males, age 65 +/- 7 yr), and four control subjects with no pulmonary diseases (Group Cont) (one female, three males, age 64 +/- 4 yr). The proportion of gland area to bronchial wall (gland%), ratio of goblet-cell occupancy to the total epithelial layer (goblet%), thickness of the basement membrane, amount of intraluminal mucus (mucus occupying ratio; MOR%), and number of various cell types per square millimeter in airway walls in a section 4 microns thick were measured in central (3 to 8 mm diameter) and peripheral airways (2 mm or less diameter). Gland% for the PE+BA group was significantly greater than that for the Cont group, whereas it did not differ significantly from that of the PE or BA groups. Goblet% and thickness of the basement membrane in central and/or peripheral airways in Group PE+BA were significantly greater than those in Group Cont, whereas those in Group PE were similar to those in Group Cont. Although not statistically significant, MOR% in central and peripheral airways from Group PE+BA showed a similar value to that in Group BA, whereas MOR% in Group PE was the same as that in Group Cont. The eosinophil number in peripheral airways walls in Group PE+BA showed a similar value to that in Group BA, which was significantly greater than in Group Cont. Other cells (macrophages, lymphocytes, and neutrophils) showed similar values among Groups PE+BA, PE, and BA. The number of eosinophils in central and/or peripheral airways correlated significantly with both goblet% and BMT, whereas other cells did not. These findings indicate that the airways of Group PE+BA are morphologically similar to those of Group BA, suggesting a combination of pulmonary emphysema with bronchial asthma.

Aged↗
PubMed1996

Comparison of computed density and microscopic morphometry in pulmonary emphysema.

The purpose of this prospective study was to verify whether the percentage area of lung occupied by lowest attenuation values on high-resolution computed tomography (HRCT) scans reflects microscopic emphysema and to compare this quantification with the information yielded by the most widely used pulmonary function tests (PFT). Preoperative HRCT scans were obtained with 1-cm intervals in 38 subjects. With a semiautomatic evaluation procedure, the percentage areas occupied by attenuation values inferior to thresholds ranging from -900 Hounsfield units (HU) to -970 HU were calculated for the lobe or lung to be resected. Emphysema was microscopically quantified by using a computer-based method, measuring the perimeters and interwall distances of alveoli and alveolar ducts. The strongest correlation was found for -950 HU. As a second step, we evaluated possible correlations between PFT and microscopic measurements. Finally, considering the microscopic measurements as a standard, we tried to investigate their relationships with each of the PFT and with the relative area occupied by attenuation values lower than -950 HU for both lungs. This revealed that the diffusing capacity for carbon monoxide associated with HRCT quantification is sufficient to predict microscopic measurements. We concluded that the percentage area of lung occupied by attenuation values lower than -950 HU is a valid index of pulmonary emphysema.

Adult↗