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Purpose: Decreased irisin levels may be associated with the development of emphysema. Similarly, emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT). We investigated the severity of emphysematous changes and the relationship between irisin levels and CLAD after bilateral LDLLT and cadaveric lung transplantation (CLT)., Methods: The subjects of this retrospective study were 59 recipients of bilateral LDLLT (n = 31) or CLT (n = 28), divided into a non-CLAD group (n = 41), a LDLLT-CLAD group (n = 11), and a CLT-CLAD group (n = 7). We compared the severity of emphysematous changes, the skeletal muscle mass, and the plasma irisin levels among the groups., Results: The emphysematous changes were significantly more severe in the LDLLT-CLAD and CLT-CLAD groups (p = 0.046 and 0.036), especially in patients with bronchiolitis obliterans syndrome (BOS), than in the non-CLAD group. Although the skeletal muscle mass was similar in all the groups, the plasma irisin levels were significantly lower in the LDLLT-CLAD group (p = 0.022), especially in the patients with BOS after LDLLT, than in the non-CLAD group., Conclusion: Emphysematous changes and lower levels of plasma irisin were associated with CLAD, especially in patients with BOS, after bilateral LDLLT., (© 2021. Springer Nature Singapore Pte Ltd.)

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.

Objectives: To study risk factors for sepsis and mortality evaluating the role of platelet to leucocytic count ratio (PLR) as a marker for urosepsis and clinical outcomes in cases of emphysematous pyelonephritis (EPN)., Materials: Patients with EPN were retrospectively reviewed. Patients' age, sex, diabetes mellitus (DM), Body Mass Index (BMI), hydronephrosis, types of EPN, air locules volume, serum creatinine, leucocytic count, and platelet count, PLR, albumin, INR and the line of treatment were analyzed as risk factors of sepsis. Correlation between PLR and other variables was done using Pearson correlation coefficient. Univariate and multivariate analyses for sepsis and mortality were performed., Results: Of fifty four patients, 38 patients had SIRS ≥2 criteria on admission. Twenty patients developed sepsis requiring ICU admission. In univariate analysis, male gender, lower BMI, higher INR, higher WBCs count and lower PLR were associated with sepsis (P = 0.0001, 0.009, 0.04, 0.003 and 0.001, respectively). In multivariate analysis, PLR ≤18.4, male sex and BMI ≤24.2 were independent risk factors. Lower PLR directly correlated with serum albumin (P = 0.01) and inversely correlated with serum creatinine and random blood glucose level and Klebsiella infection (P = 0.001, 0.007 and 0.005, respectively). Also, it was correlated with a higher total score of qSOFA and SOFA (P = 0.02 and 0.04). Lower PLR was independent risk factors for death in EPN patients with (P = 0.003)., Conclusion: EPN is associated with sepsis development. Lower PLR is an independent simple predictor for sepsis and mortality in patients with EPN., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: We established a causal relationship between indium exposure and lung interstitial and emphysematous effects. Lung cancer has been clearly demonstrated in rats and mice exposed to indium phosphide and in rats exposed to indium tin oxide. However, no information is available on human indium-related lung cancer., Methods: The baseline studies were conducted on 381 indium-exposed and 150 referent workers in 11 factories from 2003 to 2006. Items examined included indium concentration in serum (In-S), occupational history, Krebs von den Lungen-6 (KL-6), chest high-resolution computed tomography (HRCT), medical history, smoking habits, and subjective symptoms. Subjects received follow-up health checkups, and a total of 220 indium-exposed and 26 nonexposed workers were examined at least once with chest HRCT from 2013 to 2018., Results: Four lung cancer cases were identified only in indium-exposed workers. Two were prevalent cases and two were incident cases. The averages (range) of age (years), exposure duration (years), In-S (μg/L), and KL-6 (U/mL) at the baseline survey were 58 (50-74), 1.7 (0.3-4.8), 3.1 (0.3-9.7), and 663 (414-942). The mean (range) latency from initial indium exposure was 5.3 (0.4-11) years. The HRCT findings in two incident cases were mild interstitial/emphysematous change and mild interstitial change. The standardized incidence ratio (SIR) of the incident cases was 1.89 (95%CI 0.52-6.88)., Conclusions: Although the SIR was not statistically significant, there was an undeniable possibility of indium-related lung cancer due to the short follow-up duration being insufficient to disclose lung cancer and the small number of lung cancer cases. Further follow-up is necessary., (© 2019 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with endothelial dysfunction. Cadherins are adhesion molecules on epithelial (E-) and vascular endothelial (VE-) cells. Soluble (s) cadherin is released from the cell surface by the effects of proteases including matrix metalloproteinases (MMPs)., Objective: The aim of this study was to examine the associations of sE-/sVE-cadherin levels in plasma with the development of COPD., Methods: Plasma sE-/VE-cadherin levels were measured by an enzyme-linked immunosorbent assay in 115 patients with COPD, 36 symptomatic smokers (SS), 63 healthy smokers (HS) and 78 healthy non-smokers (HN). sE-cadherin and MMP-7 levels in epithelial lining fluid (ELF) were measured in 24 patients (12 COPD and 12 control)., Results: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios were significantly higher in COPD and SS than in HS and HN groups, while plasma sVE-cadherin levels were lower in COPD than in HS and HN groups (p < 0.0001). sE-cadherin levels paralleled the severity of airflow limitation in both plasma (p < 0.01) and ELF (p < 0.05), while plasma sVE-cadherin levels were inversely correlated with the extent of emphysema (p < 0.05). MMP-7 levels were correlated with sE-cadherin levels in ELF., Conclusions: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios are potential biomarkers for COPD.

The most common genotype associated with severe α-1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α-1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M. However, it is unknown whether Z AAT can co-polymerize with other AAT variants in vivo. We co-expressed two AAT variants, each modified by a different tag, in cell models that replicate AAT deficiency. We used pull-down assays to investigate interactions between co-expressed variants and showed that Z AAT forms heteropolymers with S and with the rare Mmalton (Phe52del) and Mwurzburg (Pro369Ser) mutants, and to a lesser extent with the wild-type protein. Heteropolymers were recognized by the 2C1 mAb that binds to Z polymers in vivo. There was increased intracellular accumulation of AAT variants when co-expressed with Z AAT, suggesting a dominant negative effect of the Z allele. The molecular interactions between S and Z AAT were confirmed by confocal microscopy showing their colocalization within dilated ER cisternae and by positivity in Proximity Ligation Assays. These results provide the first evidence of intracellular co-polymerization of AAT mutants and contribute to understanding the risk of liver disease in SZ and MZ heterozygotes.

Exposure to ozone has led to airway inflammation and airway hyperresponsiveness, which potential mechanisms relate to ozone-induced oxidative stress. IL-17 is a growing target for autoimmune and inflammatory diseases. The aim of the study was to examine the inhibitory effects of anti-murine interleukin-17A monoclonal antibody (IL-17mAb) on adverse effects of ozone which are noted above. After C57/BL6 mice were exposed to ozone (2.5ppm; 3h) for 12 times over 6 weeks, IL-17mAb, PBS was intraperitoneally injected into mice 1h after ozone or air exposure for 6 weeks and mice were studied 24h after final exposure, monitoring bronchial responsiveness, airway inflammatory cells, lung histology, levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage (BAL) fluid and serum, the expression of IL-17A mRNA and protein, glucocorticoid receptors (GR), and the phosphorylation of p38MAPK in lung tissues. The administration of IL-17mAb reduced the ozone-induced increases in total cells, especially neutrophils; decreased levels of cytokines, including IL-8 in BAL fluid, IL-8 and IL-17A in serum; mitigated the severity of airway hyperresponsiveness; attenuated lung inflammation scores and histologic analysis confirmed the suppression of lung inflammation, compared with the administration of a control PBS. Exposure to ozone results in increases in IL-17A production rate, mRNA and protein levels of IL-17A and the protein level of GR. These effects were halted and reversed by IL-17mAb treatment. Furthermore, IL-17mAb also reduced the phosphorylation of p38MAPK. Therefore, we conclude that IL-17mAb may be a useful therapy in ozone-related diseases, including COPD., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD., (Copyright ©ERS 2016.)

Objectives: The aim of this study was to evaluate whether pancreatic necrosis with presence of gas is an absolute indication for surgery or if there is a possibility for the medical management of this pathology., Methods: This study is a retrospective study including 56 patients with diagnosis of pancreatic necrosis and gas on computed tomography from April 2003 to March 2011. We recorded all the factors related to each group of treatment, including APACHE II score, C-reactive protein level, Tomographic Severity Index, organ and multiorgan failure, and infected necrosis after fine-needle puncture, to evaluate the differences between surgical and medical treatment., Results: Thirty-six (64%) of these patients were submitted to surgery, whereas 20 (36%) were managed conservatively. Twenty-eight patients (78%) who underwent surgery had infected necrosis. Thirty-five percent of the patients (7 patients) in the medical group had organ failure versus 83% of the patients in the surgical group., Conclusions: Pancreatic necrosis with gas on computed tomography is a relative indication for surgery. Medical management is a feasible and safe possibility for this pathology in selected cases. The presence of organ failure and infected necrosis often precludes a surgical treatment.

Pathophysiological features of chronic obstructive pulmonary disease (COPD) include systemic abnormalities, such as weight loss and skeletal muscle wasting. Although cigarette smoke (CS) is a major risk factor in COPD, the systemic effects of CS exposure remain to be elucidated. In this study, rats were exposed to CS or smoke-free air for 12 weeks. CS-exposed rats developed emphysema and had significantly lower body weight and food intake than control rats. The plasma ghrelin levels significantly increased with an upregulation of gastric ghrelin mRNA expression induced by CS exposure. Further, we observed low plasma insulin-like growth factor-1 levels and high tumor necrosis factor-α levels. A significant reduction of skeletal muscle strength and an increase in the mRNA expression of catabolic factors was observed in CS-exposed rats. These results indicated that chronic CS exposure induced not only pulmonary emphysema but also systemic abnormalities related to muscle catabolism associated with inflammatory responses., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations., Methods: Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated., Results: Individual genes were not found to be significantly associated with the number of exacerbations. However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association. A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection. Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections. The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations., Conclusion: A distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness. While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.

Background: Serum KL-6 is a useful biomarker for the diagnosis of interstitial lung diseases (ILD). However, KL-6 has not been used to discriminate different types of ILD. Serum KL-6 concentrations can vary depending on antigen exposure levels in patients with hypersensitivity pneumonitis (HP); however, seasonal changes in serum KL-6 concentrations in ILD have not been determined. We hypothesized that seasonal variation of serum KL-6 is greater in HP than for the other ILD. The aim of this study was to determine seasonal variation of serum KL-6 concentrations in various ILD., Methods: Serum KL-6 concentrations in the summer season from June 1 to September 30 and the winter season from November 1 to February 28 were retrospectively analyzed in patients with idiopathic pulmonary fibrosis (IPF, n=16), non-specific interstitial pneumonia (NSIP, n=16), collagen vascular disease-associated interstitial pneumonia (CVD-IP, n=33), house-related HP (House-HP, n=9), bird-related HP (Bird-HP, n=9), and combined pulmonary fibrosis and emphysema (CPFE, n=13)., Results: Bird-HP and House-HP showed greater seasonal serum KL-6 variation than the other ILD. Serum KL-6 concentrations in Bird-HP were significantly increased in the winter and KL-6 concentrations in House-HP were significantly increased in the summer. Serum KL-6 variation was significantly greater in acute HP than chronic HP. Receiver operating characteristic curve analysis revealed that greater seasonal variation in serum KL-6 concentrations is diagnostic for Bird-HP., Conclusion: HP should be considered in ILD with greater seasonal changes in serum KL-6 concentrations.

Interleukin-21 (IL-21) has been reported to be involved in many Th1-associated diseases. However, the alteration and immune regulation of IL-21 in emphysema remains unknown. In this study, we tested the levels of IFN-γ and IL-21 and the frequencies of Th1 and Tc1 in peripheral blood from cigarette smoke (CS)-exposed mice and air-exposed mice and explored the effect of IL-21 on generation of Th1 and Tc1 cells in vitro. It was found that the levels of IFN-γ and IL-21 and the frequencies of Th1, Tc1, CD4(+) IL-21(+), CD4(+) IL-21R(+), and CD8(+) IL-21R(+) T cells were much higher in CS-exposed mice. Moreover, the levels of IL-21 were correlated positively with Th1 cells and with Tc1 cells. Finally, the in vitro experiments showed that IL-21 could promote Th1/Tc1 cell generation in CS-exposed mice. These results indirectly provide evidence that IL-21 produced by CD4(+) T cells could promote Th1/Tc1 response, leading to systemic inflammation in emphysema.

Context: Ceramide causes endothelial apoptosis and emphysema-like changes in animal models., Objectives: Test if plasma sphingomyelin, a major precursor of ceramide, would predict longitudinal increase in the percentage of emphysema-like lung on computed tomography (CT)., Materials and Methods: 3840 participants had their plasma sphingomyelin measured at baseline examination and their pulmonary emphysema measured on cardiac CT scans at baseline and on follow-up visits. Mixed effects models were used to adjust for potential confounders., Results: One standard deviation increase in sphingomyelin predicted a 0.12% per year (95% CI: 0.02-0.22; p = 0.019) greater increase of percent emphysema., Discussion and Conclusion: Higher plasma levels of sphingomyelin predicted greater annual increase in quantitatively measured percent emphysema.

Heavy smoking is associated with the development of chronic obstructive pulmonary disease (COPD). However, there is no valuable biomarker for evaluating COPD development in heavy smokers because they are usually asymptomatic. This study is aimed at evaluating whether the levels of serum miRNAs can serve as biomarkers for predicting the occurrence of COPD. A rat model of emphysema was induced by enforced smoking, and the dynamic miRNAs expression profile at different stages of emphysema with varying periods of smoking were analyzed by microarray and quantitative real-time polymerase chain reaction (qRT-PCR). The differentially expressing miRNAs were analyzed using Gene Ontology and the KEGG PATHWAY database. The levels of three serum candidate miRNAs were measured by qRT-PCR in 41 healthy controls (HC), 40 asymptomatic heavy smokers, and 49 COPD patients. Following smoking for varying periods, different severities of lung emphysema were observed in different groups of rats, accompanied by altered levels of some serum miRNAs associated with regulating some pathways. Furthermore, the levels of miR-21 were significantly higher in the COPD patients and asymptomatic heavy smokers than in the HC (P < 0.001), while the levels of miR-181a were significantly lower in the COPD patients and asymptomatic heavy smokers than in the HC (P < 0.001). Accordingly, the levels of serum miR-21 and miR-181a as well as their ratios had a high sensitivity (0.854) and specificity (0.850) for evaluating the development of COPD. Our data suggest that the levels of serum miR-21 and miR-181a may be valuable for evaluating the development of COPD in heavy smokers.

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema.

Objective: The Alpha-1 Foundation convened a workshop to consider the appropriateness of newborn screening for α-1-antitrypsin (AAT) deficiency., Methods: A review of natural history and technical data was conducted., Results: Homozygous ZZ AAT deficiency is a common genetic disease occurring in 1 in 2000 to 3500 births; however, it is underrecognized and most patients are undiagnosed. AAT deficiency can cause chronic liver disease, cirrhosis, and liver failure in children and adults, and lung disease in adults. The clinical course is highly variable. Some neonates present with cholestatic hepatitis and some children require liver transplantation, but many patients remain well into adulthood. Some adults develop emphysema. There is no treatment for AAT liver disease, other than supportive care and liver transplant. There are no data on the effect of early diagnosis on liver disease. Avoidance of smoking is of proven benefit to reduce future lung disease, as is protein replacement therapy. Justifying newborn screening with the aim of reducing smoking and reducing adult lung disease-years in the future would be a significant paradigm shift for the screening field. Recent passage of the Genetic Information Nondiscrimination Act (GINA) and the Affordable Care Act may have a major effect on reducing the psychosocial and financial risks of newborn screening because many asymptomatic children would be identified. Data on the risk-benefit ratio of screening in the new legal climate are lacking., Conclusions: Workshop participants recommended a series of pilot studies focused on generating new data on the risks and benefits of newborn screening.

Secondhand smoke (SHS) has been associated with a variety of adverse health outcomes in nonsmokers, including emphysema (a chronic obstructive pulmonary disease). One way to detect SHS exposure is to measure the concentration of cotinine, the primary metabolite of nicotine, in bodily fluids. We have developed a method for cotinine analysis by combining micellar electrokinetic chromatography with enrichment techniques. We employed the method to measure cotinine concentrations in serum samples of mice exposed to tobacco smoke for 12 or 24 weeks and found that it was 3.1-fold or 4.8-fold higher than those exposed to room air for the same period. Further, we investigated the morphological changes in lungs of mice and observed tobacco smoke induced emphysema. Our results indicate that the method can be used to measure cotinine and there is an association between the serum cotinine concentration and tobacco smoke-induced emphysema in mice.

Interleukin-16 (IL-16) is a multifunctional cytokine that has been associated with autoimmune and allergic diseases. To investigate comprehensively whether IL-16 is also associated with chronic obstructive pulmonary disease (COPD) and emphysema, we performed an integrated analysis of multiple "omics" data. Over 500 subjects participating in the COPDGene® study donated blood and were clinically characterized and genetically profiled. IL-16 mRNA levels were measured in peripheral blood mononuclear cells (PBMC), and protein levels were measured in fresh frozen plasma. A multivariate analysis found plasma IL-16 positively associated with age and body mass index, and negatively associated with current smoking and emphysema in the upper lobes. PBMC IL-16 expression was positively associated with gender and a composite score for airflow obstruction, emphysema, and gas trapping. Whole-genome expression quantitative trait locus (eQTL) analysis identified a novel IL-16 missense SNP (rs11556218) associated with lower IL-16 in plasma. In summary, an integrated "omics" analysis in a very large cohort identified an association between decreased IL-16 and emphysema and discovered a novel IL-16 cis-eQTL. Thus IL-16 plasma levels and IL-16 genotyping may be useful in a personalized medicine approach for lung disease.

Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost., Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics., Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated., Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10(-16)), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbon monoxide (P = 0.01) in the TESRA study., Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder associated with systemic manifestations that contribute to its morbidity and mortality. Recent work suggests that biomarker signatures in the blood may be useful in evaluating COPD phenotypes and may provide insight into the pathophysiology of systemic manifestations. Adiponectin, primarily produced by fat cells, has been implicated in the pathophysiology of emphysema., Objectives: To investigate the association of adiponectin with clinical and radiologic COPD phenotypes., Methods: Adiponectin levels were determined in 633 individuals, including 432 individuals with COPD from a cohort of former or current smokers enrolled in the COPDGene study. Univariate and multiple regression analysis were used to examine the association of adiponectin with clinical and physiologic data together with quantitative high-resolution computed tomography parameters., Measurements and Main Results: Multiple regression analysis confirmed that higher plasma adiponectin levels were independently associated with emphysema, decreasing body mass index, female sex, older age, and lower percentage change in prebronchodilator/post-bronchodilator FEV1., Conclusions: The association between plasma adiponectin and computed tomography-assessed emphysema suggests a contribution of adiponectin to the development of emphysema and highlights a role for metabolic derangements in the pathophysiology of emphysema.

The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly appreciated. In this study, we identified serum autoantibody reactivities associated with chronic bronchitis or emphysema, as well as systemic autoimmunity and associated lung disease. Using autoantigen array analysis, we demonstrated that COPD patients produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype. Patients with emphysema produced autoantibodies of higher titer and reactive to an increased number of array antigens. Strikingly, the autoantibody reactivities observed in emphysema were increased over those detected in rheumatoid arthritis patients, and included similar reactivities to those associated with lupus. These findings raise the possibility that autoantibody profiles may be used to determine COPD risk, as well as provide a diagnostic and prognostic tool. They shed light on the heterogeneity of autoantibody reactivities associated with COPD phenotype and could be of use in the personalization of medical treatment, including determining and monitoring therapeutic interventions.

Background: Cystatin C (CysC) is a potent nonorgan-specific cysteine protease inhibitor and may contribute to elastolysis and tissue destruction by a mechanism of protease–antiprotease imbalance. Given the prevalence of CysC in the serum of smokers and its role in tissue destruction, we aimed to evaluate the association between CysC and emphysema., Methods: Pooled cross-sectional data from the National Health and Nutrition Examination Survey 1999–2002 were used. Emphysema and chronic bronchitis were defined by a self-reported history ascertained using standardized questionnaires. Active smokers were defined as self-reported current smokers or measured serum cotinine ≥10 ng/mL. Nonactive smokers with a serum cotinine level >0.05 ng/mL were defined as environmental tobacco smoke (ETS)-exposed., Results: The prevalence (95% CI) of emphysema was 1.3% (range = 0.9–1.8%). The mean (SE) CysC level in the emphysema group was significantly higher than in normal controls [1,139 (22) vs. 883 (8) μg/L; p = 0.001]. Upon stratification of the study population by C-reactive protein (CRP) concentrations, we demonstrated a progressive increase in the mean serum CysC level with serially increasing CRP concentrations. Active smokers with emphysema had 115.4 (46.5) μg/L higher mean (SE) CysC levels than the normal controls (p < 0.001). Upon adjusted analysis, we observed that nonactive smokers with significant ETS exposure had 31.2 (15.2) μg/L higher mean (SE) serum CysC levels as compared to ETS unexposed nonactive smokers (p = 0.04)., Conclusion: In a large representative noninstitutionalized US population, we demonstrated an association between emphysema and serum CysC. Active smokers with emphysema had significantly higher CysC levels. These findings suggest that CysC may play a role in the pathogenesis of smoking-related emphysema.

Background: Osteoporosis is one of the systemic features of COPD. A correlation between the emphysema phenotype of COPD and reduced bone mineral density (BMD) is suggested by some studies, however, the mechanisms underlying this relationship are unclear. Experimental studies indicate that IL-1β, IL-6 and TNF-α may play important roles in the etiology of both osteoporosis and emphysema. The OPG/RANK/RANKL system is an important regulator of bone metabolism, and participates in the development of post-menopausal osteoporosis. Whether the OPG/RANK/RANKL pathway is involved in the pathogenesis of osteoporosis in COPD has not been studied., Methods: Eighty male patients (current or former smokers) completed a chest CT scan, pulmonary function test, dual x-ray absorptiometry measurements and questionnaires. Among these subjects, thirty patients with normal BMD and thirty patients with low BMD were selected randomly for measurement of IL-1β, IL-6, TNF-α (flow cytometry) and OPG/RANK/RANKL (ELISA). Twenty age-matched healthy volunteers were recruited as controls., Results: Among these eighty patients, thirty-six had normal BMD and forty-four had low BMD. Age, BMI and CAT score showed significant differences between these two COPD groups (p < 0.05). The low-attenuation area (LAA%) in the lungs of COPD patients was negatively correlated with lumbar vertebral BMD (r = 0.741; p < 0.0001). Forward logistic regression analysis showed that only LAA% (p = 0.005) and BMI (p = 0.009) were selected as explanatory variables. The level of IL-1β was significantly higher in the COPD patients as compared to the normal controls (p < 0.05), but the difference between the two COPD groups did not reach significance. The levels of IL-6 and TNF-α among the three groups were significantly different (p < 0.05). The level of RANKL and the RANKL/OPG ratio were significantly higher in COPD patients with low BMD compared to those with normal BMD and the normal controls (p < 0.05), and correlated negatively with lumbar vertebral BMD, but positively with LAA%., Conclusions: Radiographic emphysema is correlated with low BMD in current and former smokers with COPD. IL-1β, IL-6, TNF-α, and the osteoporosis-related protein system OPG/RANK/RANKL may have some synergetic effects on emphysema and bone loss in COPD.

Introduction: The relation of AAT phenotype and COPD still raises lots of controversy. In this study we aimed to investigate relation lung function characteristics, AAT serum level and COPD in smoking and non smoking population., Patients and Methods: This was a prospective non-randomized study in which we evaluated 45 patients with severe (stage IV) COPD. In all patients we determined AAT phenotype, serum AAT levels and lung function tests. We correlated findings in relation to the smoking status., Results: All patients were MM type homozygotes. Serum AAT concentrations were within the reference values, amounting to 1.66g/l in smokers and 1.80g/l in nonsmokers. There was no significant correlation between serum AAT concentrations and lung function parameters. We have observed the higher mean values of ITGV, RV, TLC and RV/TLC in smokers and a statistically significant difference only in ITGV., Conclusion: All of the investigated patients with severe COPD were MM type homozygotes with normal plasma level of AAT. There was no significant correlation between the phenotype and severity of COPD. We did not find significant relation of plasma AAT level and lung function impairment., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: To develop a sleep hypoxia (SH) in emphysema (SHE) rat model and to explore whether SHE results in more severe hepatic inflammation than emphysema alone and whether the inflammation changes levels of coagulant/anticoagulant factors synthesized in the liver., Methods: Seventy-five rats were put into 5 groups: SH control (SHCtrl), treated with sham smoke exposure (16 weeks) and SH exposure (12.5% O(2), 3 h/d, latter 8 weeks); emphysema control (ECtrl), smoke exposure and sham SH exposure (21% O(2)); short SHE (SHEShort), smoke exposure and short SH exposure (1.5 h/d); mild SHE (SHEMild), smoke exposure and mild SH exposure (15% O(2)); standard SHE (SHEStand), smoke exposure and SH exposure. Therefore, ECtrl, SHEShort, SHEMild and SHEStand group were among emphysematous groups. Arterial blood gas (ABG) data was obtained during preliminary tests. After exposure, hepatic inflammation (interleukin -6 [IL-6] mRNA and protein, tumor necrosis factor α [TNFα] mRNA and protein) and liver coagulant/anticoagulant factors (antithrombin [AT], fibrinogen [FIB] and Factor VIII [F VIII]) were evaluated. SPSS 11.5 software was used for statistical analysis., Results: Characteristics of emphysema were obvious in emphysematous groups and ABGs reached SH criteria on hypoxia exposure. Hepatic inflammation parameters and coagulant factors are the lowest in SHCtrl and the highest in SHEStand while AT is the highest in SHCtrl and the lowest in SHEStand. Inflammatory cytokines of liver correlate well with coagulant factors positively and with AT negatively., Conclusions: When SH is combined with emphysema, hepatic inflammation and coagulability enhance each other synergistically and produce a more significant liver-derivative inflammatory and prothrombotic status.

Rationale: In emphysema, chronic inflammation, including protease-antiprotease imbalance, is responsible for declining pulmonary function and progressive cachexia., Objectives: To evaluate variations of inflammatory mediators and alpha(1)-antitrypsin levels after lung volume reduction surgery (LVRS) compared with respiratory rehabilitation., Methods: A total of 28 patients with moderate to severe emphysema, who underwent video-assisted thoracoscopic LVRS, were compared with 26 similar patients, who refused operation and followed a standardized rehabilitation program, and to a matched healthy group. Respiratory function, body composition, circulating inflammatory mediators, and alpha(1)-antitrypsin levels were evaluated before and 12 months after treatment. Gene expression levels of inflammatory mediators and protease-antiprotease were assessed in emphysematous specimens from 17 operated patients by matching to normal tissue from resection margins., Measurements and Main Results: Significant improvements were only obtained after surgery in respiratory function (FEV(1), +25.2%, P < 0.0001; residual volume [RV], -19.5%, P < 0.0001; diffusing lung capacity for carbon monoxide, +3.3%, P < 0.05) and body composition (fat-free mass, +6.5%, P < 0.01; fat mass, +11.9%, P < 0.01), with decrement of circulating inflammatory mediators (TNF-alpha, -22.2%, P < 0.001; IL-6, -24.5%, P < 0.001; IL-8, -20.0%, P < 0.001) and increment of antiprotease levels (alpha(1)-antitrypsin, +27.0%, P < 0.001). Supportive gene expression analysis demonstrated active inflammation and protease hyperactivity in the resected emphysematous tissue. Reduction of TNF-alpha and IL-6 and increment of alpha(1)-antitrypsin levels significantly correlated with reduction of RV (P = 0.03, P = 0.009, and P = 0.001, respectively), and partially with increment of fat-free mass (P = 0.03, P = 0.02, and P = 0.09, respectively)., Conclusions: LVRS significantly reduced circulating inflammatory mediators and increased antiprotease levels over respiratory rehabilitation, also improving respiratory function and nutritional status. Correlations of inflammatory mediators and antiprotease levels with RV and, partly, with body composition suggest that elimination of inflammatory emphysematous tissue may explain clinical improvements after surgery.

Deficiency of alpha-1-antitrypsin (alpha(1)-AT, a major protease inhibitor controlling tissue degradation) is a genetic disorder transmitted in a codominant autosomal form. It has more than 100 genetically determined variants. This study attempted to determine the degree of association between serum alpha(1)-AT levels and phenotypes and to provide a strategy for reliable laboratory evaluation of deficiencies. The study group consisted of a 38-year-old male proband with clinical features of emphysema, his first-degree relatives, and healthy controls. Family history revealed a four-generation pedigree. Genomic DNA was isolated from peripheral blood leukocytes. Alpha-1-AT levels were determined from human serum by immunonephelometry. Phenotypes were determined by isoelectric focusing of blood samples. DNA sequences of coding exons were analyzed by the amplification DNA technique and direct sequencing. Inheritance and plasma levels of the ZZ, MM, M3S, and MZ phenotypes were confirmed by the family study. In the family members with deficiencies, plasma concentrations were 22.55% +/- 5.15 (ZZ), 84.18% +/- 5.18 (M3S), and 61.06% +/- 7.15 (MZ) of the normal MM level. We found a close association between alpha(1)-AT level and genotype. A combination of genotyping, quantification, and phenotyping is the optimal strategy for the laboratory evaluation of alpha(1)-AT deficiency.

Laboratory diagnosis of alpha-1-antitrypsin (AAT) deficiency is routinely performed by phenotyping methods, which include measurement of serum alpha-1-antitrypsin concentration and isoelectric focusing (IEF). Several DNA-based methods are also used for AAT deficiency testing, but they still have not become part of routine diagnostics. The aim of the study was to identify AAT variants using 2 different methods, isoelectric focusing and denaturing gradient gel electrophoresis (DGGE), and to compare obtained results as well as practical application of these 2 methods. The study has encompassed 27 emphysema patients. In all patients, AAT phenotypization was conducted using IEF, whereas genotypization was performed by DGGE. Variations detected by DGGE were characterized by DNA sequencing. Mutations in the AAT gene were detected in 6 patients. Three patients were homozygous for the Z allele, whereas 1 patient was heterozygous. In 2 patients, novel AAT variants, G320R and V321F, were detected. When results obtained by IEF and DGGE were compared, it was observed that IEF results were inconclusive or misinterpreted in 5 cases (18.5%). Both methods proved to be reliable for detection of the Z alleles, whereas discrepancy existed for M4 allele and rare variants. Therefore, the optimal strategy for diagnostics of AAT deficiency should encompass detection of the most common AAT variants by IEF and screening for the less common variants by DGGE in combination with sequencing.

We describe the case of a 24-year old male who had been a heavy smoker since the age of 9 and who presented with an 8-year history of respiratory symptoms. He was having treatment for asthma. Spirometric studies and high-resolution computed tomography (HRCT) scans confirmed COPD with centrilobular emphysema. His blood level of alpha-1-antitrypsin was within the normal range. Early onset emphysema in smokers with a normal alpha-1-antitrypsin has been previously described. However, this case is, as far as we know, one of the youngest cases ever reported.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by varying degrees of airflow limitation and diffusion impairment. There is increasing evidence to suggest that COPD is also characterized by systemic inflammation. The primary goal of this study was to identify soluble proteins in plasma that associate with the severity of airflow limitation in a COPD cohort with stable disease. A secondary goal was to assess whether unique markers associate with diffusion impairment, based on diffusion capacity of carbon monoxide (DLCO), independent of the forced expiratory volume in 1 second (FEV1)., Methods: A cross sectional study of 73 COPD subjects was performed in order to examine the association of 25 different plasma proteins with the severity of lung function impairment, as defined by the baseline measurements of the % predicted FEV1 and the % predicted DLCO. Plasma protein concentrations were assayed using multiplexed immunobead-based cytokine profiling. Associations between lung function and protein concentrations were adjusted for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use., Results: Plasma concentrations of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1), CCL4/macrophage inflammatory protein-1 beta (CCL4/MIP-1 beta), CCL11/eotaxin, and interleukin-13 (IL-13) were inversely associated with the % FEV1. Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-gamma (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL-13 showed inverse relationships with the % DLCO., Conclusion: Systemic inflammation in a COPD cohort is characterized by cytokines implicated in inflammatory cell recruitment and airway remodeling. Plasma concentrations of IL-13 and chemoattractants for monocytes, T lymphocytes, and eosinophils show associations with increasing severity of disease. Soluble Fas, G-CSF and CXCL9/Mig may be unique markers that associate with disease characterized by disproportionate abnormalities in DLCO independent of the FEV1.

Pulmonary emphysema is a major component of the morbidity and mortality of chronic obstructive pulmonary disease (COPD). Currently there are no predictive biomarkers for COPD. Initial steps toward identifying potentially predictive biomarkers involve utilizing well-characterized mainstream smoke (MS) exposure conditions (dose-response) to identify changes in biomarkers of effect (inflammation, tissue injury, oxidative stress) in emphysema-susceptible and -resistant mouse strains. C57Bl/6 mice have been reported to develop emphysema when exposed chronically to cigarette smoke, while similarly exposed ICR mice do not. Male C57Bl/6 and ICR mice were exposed 2 h/day for 7 consecutive days to MS from a standard reference cigarette (2R4F) at 75, 250, and 600 microg total particulate matter (TPM)/L or filtered air. To confirm exposure, blood samples were collected toward the end of the last exposure and analyzed for carboxyhemoglobin, nicotine, and cotinine. Bronchoalveolar lavage (BAL) fluid samples were collected 2 or 12 h postexposure and analyzed for biomarkers of effect. MS dose differed slightly between strains. More necrosis was observed in nasal epithelium of exposed C57Bl/6 mice. Exposure concentration-dependent increases in apoptosis, chemokines, and neutrophil counts were greater in ICR mice. Similar increases in thymus and activated-regulated chemokine were only observed in C57Bl/6 mice. BAL fluid cells of C57Bl/6 mice appear to undergo necrosis, while the BAL fluid cells of ICR mice appear to undergo apoptosis following MS exposure. Utilizing two strains of mice we identified MS-responsive biomarkers of effect that may be predictive of COPD pathology. Chronic MS exposures are needed to link these biomarkers with emphysema., (Copyright Taylor & Francis Inc.)

We present a case of surgery in a 2-month-old infant of the Jehovah's Witness (JW) faith weighing 2.8 kg scheduled for left upper lobectomy because of congenital lobar emphysema. He presented with physiological anaemia (haematocrit 33.8%) in accordance with his age. Because of the relative emergency of surgery, a short erythropoietin course was instituted. Recombinant human erythropoietin (rHuEPO) at a dosage of 180 U x kg-1x day-1 was administered for 10 days preoperatively and for 4 days postoperatively. Iron was administered orally and intravenously over the entire perioperative period. No side-effects from either erythropoietin or intravenously administered iron were observed. To our knowledge, this is the first case published of a short perioperative rHuEPO course in an infant.

Objectives: This study investigated (i) whether adequate concentrations of secretory leukocyte proteinase inhibitor (SLPI) in the lungs of alpha-1-antitrypsin (A1AT) deficient patients can explain the variability in the development of emphysema in these individuals, and (ii) whether cigarette smoking jeopardises the protective screen provided by functional SLPI., Methodology: Four subjects [two normal proteinase inhibitor M (PiM), two abnormal PiZ] were selected from patients presenting for diagnostic bronchoscopy and lung function testing (spirometry, DLco). Each subject underwent BAL and had blood taken for A1AT and SLPI estimation., Results: As expected serum and BAL A1AT concentrations were within the normal range in the normal PiM subjects. In normal subjects, SLPI concentrations in serum and BAL were within the normal range. A1AT-deficient subjects had reduced serum and BAL levels of A1AT reflecting their genetic disorder but showed increased concentrations of SLPI in BAL and serum. Percentage neutrophil elastase (NE) inhibitory capacity of BAL fluid was low in both A1AT-deficient subjects and a cigarette-smoking normal subject. In contrast, the NE inhibitory capacity for the normal subject who had never smoked was normal., Conclusions: These findings suggest that in A1AT deficiency there may be a compensatory increase in SLPI. This may protect the lung against the development of emphysema in A1AT-deficient individuals. Cigarette smokers may have a lower SLPI concentration than non-smokers. This provides an explanation for at least some of the observed variation in the development of emphysema in A1AT deficient subjects.

Purpose: We identified and quantified prognostic factors for emphysematous pyelonephritis., Materials and Methods: The clinical information, laboratory data and radiological findings from 38 patients with emphysematous pyelonephritis were retrospectively analyzed., Results: There were no significant differences between the nonsurvivor and survivor groups with respect to age, gender, diabetes mellitus history, presence of bacteremia, identity of infecting organisms, blood glucose level, leukocyte count, urinary white blood count, presence or absence of urinary tract obstruction or urolithiasis, and modes of treatment. There were significant differences between the nonsurvivor and survivor groups, however, with respect to platelet count (84,300 +/- 119,500 versus 220,400 +/- 161,800/mm.3, p = 0.001), serum creatinine level (3.61 +/- 1.25 versus 2.19 +/- 1.32 mg./dl., p = 0.003) and urinary red blood counts (56.47 +/- 41.86 versus 27.65 +/- 36.14, p = 0.028). Patients with radiological type I emphysematous pyelonephritis were significantly more likely to die than those with type II (69 versus 18%, p = 0.002)., Conclusions: Serum creatinine level is the most reliable predictor of outcome in patients with emphysematous pyelonephritis. By calculating likelihood ratios, patients with creatinine levels greater than 1.4 mg./dl. and platelet counts 60,000/mm.3 or less were at high risk. The posttest probability of death increased from 69 and 18% to 92 and 53% for type I and II emphysematous pyelonephritis, respectively. Patients with creatinine levels 1.4 mg./dl. or less and platelet counts greater than 60,000/mm.3 were at much lower risk. Posttest mortality risk in these patients dropped from 69 and 18% to 27 and 4% for type I and II emphysematous pyelonephritis, respectively.

A 34-year-old man with pulmonary emphysema was found to have a mild alpha 1 proteinase inhibitor (alpha 1 PI) deficiency. alpha 1 PI status was investigated in this patient and in 35 members of his family. The alpha 1 PI investigations included alpha 1 PI concentration and phenotype and serum inhibitory capacity for trypsin and pancreatic elastase. Fifteen members of the family had alpha 1 PI concentration and inhibitory capacities below the lower normal limit. Five of these members were characterized by the heterozygous MP phenotype and the 10 others by an apparently homozygous M phenotype, in which the M allele may be associated with another unidentified deficiency allele. Two members of the family had alpha 1 PI concentration and elastase inhibitory capacity below the lower normal limits and trypsin inhibitory capacity within the normal range. They were both characterized by the MP phenotype. Six of these 17 members (three of PI type M and three of PI type MP) showed chronic pulmonary symptoms, whereas among the 19 alpha 1 PI non deficient members, no member had a history of significant pulmonary symptoms.

We investigated the concentration of ceruloplasmin (CP), transferrin (T) and metal ions (Cu, Zn) in serum of healthy smokers, emphysema patients and healty non-smoking subjects (control). We observed elevated Cu concentration in smokers and emphysema patients. Elevated CP concentration was observed only in those emphysema patients who smoked cigarettes, but not in healthy smokers. This observation excludes the possibility of compensative CP and Cu increase as the effect of chronic oxidant exposure. Changes in concentration of CP and Cu observed by us are probably due to chronic inflammation of respiratory tract not only of emphysema patients but also of chronic smokers without signs of the disease.

Haptoglobin (HP) groups were determined in Chinese patients suffering from eight different diseases and compared to those of 552 control subjects. Patients with cirrhosis of the liver showed a significant difference from controls in the distribution of HP types (p = 2 x 10(-4)), with increases in the HP*1 allele and HP1-1 phenotype frequencies. The relative risk for the HP1-1 phenotype was 3.3.

The tight-skin (Tsk) mouse is a model of genetically determined emphysema. The cause for the development of the lung lesion is unknown. In the present study we investigated the lung morphometry and the serum elastase inhibitory capacity (EIC) of Tsk mice. Mean interalveolar distance was significantly greater (+60%) in Tsk mice than in C57 Bl/6J, NMRI, and Balb/c mice, which have similar values. Serum of Tsk mice against mouse leukocyte elastase (MLE) has significantly lower EIC values than that of NMRI, Balb/c (-64%), and C57 Bl/6J (-50%) mice. Similar results were obtained when porcine pancreatic elastase (PPE) was used. Against human leukocyte elastase (HLE), however, there was no difference among the strains, all of which had high EIC values. Preincubation of mouse (C57 Bl/6J) serum with chloramine-T (CT) resulted in an almost complete inhibition of EIC against MLE and PPE but only in a 20% inhibition against HLE using a synthetic substrate. Using elastin Congo Red as substrate, CT inhibited EIC against MLE and PPE by approximately 70% but did not affect the EIC against HLE. These results indicate that (1) the Tsk mouse can be considered a model of severe inborn deficiency of serum antielastase activity which is associated with emphysema; and (2) MLE and PPE can be considered interchangeable in studies of serum EIC in the mouse. On the other hand, the differences between MLE and HLE preclude the use of HLE for EIC determination in this species.

The null-null phenotype of alpha 1-antitrypsin (alpha 1AT), a phenotype characterized by no detectable alpha 1AT in serum, presents a rare opportunity to examine the contribution of alpha 1AT to the antineutrophil elastase protection of the lower respiratory tract. The subject, a 35-yr-old lifetime non-smoker with moderate emphysema, has been characterized as having alpha 1AT serum levels of zero resulting from the homozygous inheritance of alpha 1AT genes that do not express detectable alpha 1AT mRNA transcripts. Evaluation of the antineutrophil elastase capacity of the null-null serum showed it was less than 5% of normal, whereas that of the epithelial lining fluid (ELF) of the lower respiratory tract was 13% of normal. However, after 60 mg/kg of intravenously administered alpha 1AT augmentation therapy once weekly for 4 wk, the serum alpha 1AT levels peaked at greater than 300 mg/dl, trough levels just prior to the next infusion were 81 +/- 2 mg/dl, and the average serum level integrated for the month of infusions was 138 mg/dl. Consistent with this serum rise in alpha 1AT, the serum antineutrophil elastase capacity increased in parallel(r = 0.98). Importantly, evaluation of the ELF 2 and 6 days after infusion demonstrated increases of alpha 1AT levels (range, 1.4 to 2.1 microM) and antineutrophil elastase capacity (range, 1.6 to 2.5 microM), values within the lower range of normal. Furthermore, the lung ELF alpha 1AT levels rose in direct proportion to the serum alpha 1AT levels, and the ELF antineutrophil elastase capacity rose in direct proportion to the ELF alpha 1AT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum alpha 2-macroglobulin concentrations were measured in 178 patients with emphysema and 115 control subjects of similar age and sex distribution. The study group included 59 PI type Z patients with alpha 1-antitrypsin deficiency, five with the rare alpha 1-antitrypsin null genotype (PI Q0 or --), and seven with alpha 1-antitrypsin deficiency of the rare PI types MmaltonZ or MduarteZ. Individuals with all types of alpha 1-antitrypsin deficiency were found to have significantly increased serum concentrations of alpha 2M (p less than 0.001). These increased concentrations were associated with all types of alpha 1-antitrypsin deficiency, not only with the PI type Z. The highest alpha 2-macroglobulin concentrations were found in the PI Q0 patients (5 with emphysema, 2 with no lung disease), and these patients had almost no circulating alpha 1-antitrypsin. Raised concentrations of serum alpha 2-macroglobulin were not due to emphysema: 86 patients with emphysema, of PI type M, and the normal control subjects had similar average concentrations of alpha 2-macroglobulin. One control subject with an average alpha 2-macroglobulin concentration of only 41% of normal was found.

Follow-up assessments were done in 18 patients with chronic obstructive airways disease, mainly chronic obstructive bronchitis, over a mean of 9.4 (6-18) years. Two hospital admissions were required for periods of three years. In addition, 5 of the patients had concomitant severe emphysema (chronic obstructive emphysematous bronchitis). During the observation period development of emphysema and airways resistance had not increased to any measurable degree. The patients' mean age by the end of the study was 63.6 years. Reversibility of the disease could not be influenced during clinical treatment. Patients with serious emphysema had neither worse airways resistances nor worse arterial blood gases than patients with obstructive airways disease without emphysema. As expression of increasing distribution disorder only arterial oxygen pressure decreased during the observation period when compared to normal age-related changes. The investigation demonstrates the great relevance of persistent treatment for prevention of exacerbations as well as for interval periods. This has decisively influenced the course of the disease: life expectancy of patients has clearly improved as respiratory function can be maintained constant over many years.

Severe lung disease and liver disease are not recognised features of the PiMZ phenotype, which is associated with alpha 1 antitrypsin deficiency. A 31 year old woman with this phenotype was found to have emphysema and complete heart block and showed evidence of hepatic cirrhosis, although her three sisters, all of whom had the same phenotype, were clinically normal. This case supports the possibility of a causal relation between the PiMZ phenotype and chronic lung and liver disease, but an association between alpha 1 antitrypsin deficiency and complete heart block could not be proved in this patient.