Pathological changes in the COPD lung mesenchyme--novel lessons learned from in vitro and in vivo studies.

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death worldwide and, in contrast to the trend for cardiovascular diseases, mortality rates still continue to climb. This increase is in part due to an aging population, being expanded by the "Baby boomer" generation who grew up when smoking rates were at their peak and by people in developing countries living longer. Sadly, there has been a disheartening lack of new therapeutic approaches to counteract the progressive decline in lung function associated with the disease that leads to disability and death. COPD is characterized by irreversible chronic airflow limitation that is caused by emphysematous destruction of lung elastic tissue and/or obstruction in the small airways due to occlusion of their lumen by inflammatory mucus exudates, narrowing and obliteration. These lesions are mainly produced by the response of the tissue to the repetitive inhalational injury inflicted by noxious gases, including cigarette smoke, which involves interaction between infiltrating inflammatory immune cells, resident cells (e.g. epithelial cells and fibroblasts) and the extra cellular matrix. This interaction leads to tissue destruction and airway remodeling with changes in elastin and collagen, such that the epithelial-mesenchymal trophic unit is dysregulated in both the disease pathologies. This review focuses on: 1--novel inflammatory and remodeling factors that are altered in COPD; 2--in vitro and in vivo models to understand the mechanism whereby the extra cellular matrix environment in altered in COPD; and 3--COPD in the context of wound-repair tissue responses, with a focus on the regulation of mesenchymal cell fate and phenotype.

Variation in iron homeostasis genes between patients with ARDS and healthy control subjects.

BACKGROUND: Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies. Evidence suggests that genetic predisposition is relevant to the pathogenesis of ARDS. We therefore explored the hypothesis that polymorphisms from a panel of genes encoding iron-metabolizing proteins determine susceptibility to ARDS. METHODS: Retrospective case-control study conducted at the adult ICUs of two university hospitals. Patients with ARDS (n = 122) and healthy control subjects (n = 193) were genotyped. Sequence-specific primer polymerase chain reaction was used to genotype selected biallelic single-nucleotide polymorphisms. An audit of the patient database was conducted, and 104 of the 122 ARDS patients were eligible for the final data analysis. RESULTS: Preliminary analysis indicated differences between ARDS and healthy control subjects in the incidence of polymorphism of the gene encoding ferritin light chain. Subgroup analysis indicated the prevalence of ferritin light-chain gene -3381GG homozygotes was increased in patients with ARDS of extrapulmonary origin compared to healthy control subjects. Secondly, a common haplotype in the heme oxygenase 2 gene was reduced in patients with ARDS compared to healthy control subjects and was more evident in those with ARDS of direct or pulmonary etiology. CONCLUSIONS: These results provide preliminary evidence to suggest a distinction in the genetic background of the subpopulations studied, inferring that the ferritin light-chain gene genotype confers susceptibility to ARDS, while the heme oxygenase 2 haplotype is protective against the onset of the syndrome. Such data support further previous findings that suggest abnormalities in iron handling resulting in redox imbalance are implicated in the pathogenesis of ARDS.

TNF-857T, a genetic risk marker for acute anterior uveitis.

PURPOSE: To determine the association between 17 single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha, lymphotoxin-alpha, and the TNF-receptors genes (TNF, LTA, and TNFRSF1A and -B) and idiopathic acute anterior uveitis (IAU) and to investigate their association with HLA-B27 and/or the development of visually significant complications. METHODS: Ninety-eight white patients in the United Kingdom were identified (by SL) from the uveitis clinics of Moorfields Eye Hospital (London, UK). Sequence-specific primers with 3' end mismatches were used to identify the presence of specific allelic variants by PCR amplification. RESULTS: There was a significant increase in the frequency of the TNF-857T allele in patients with IAU when compared with control subjects (15.3% vs. 7.3%, P = 0.0006). The frequency of haplotype 4, containing the T allele at nucleotide position -857, was also significantly increased in patients with IAU compared with control subjects (15.4% vs. 7.1%, P = 0.0003, OR 2.4, 95% confidence interval 1.4-4.0). In subgroup analysis, there were significant differences in the frequencies of the uncommon TNFRSF1A-201T and TNFRSF1A-1135T alleles between HLA-B27(+) patients with inflammation-related complications and those without complications (80.0% vs. 33.6%, P = 0.006; 80.0% vs. 36.6%, P = 0.01, respectively). CONCLUSIONS: A significant difference in the frequency of TNF-857T allele was found in patients with IAU. There was a trend toward the development of inflammation-related complications in HLA-B27(+) patients with IAU who were carriers of TNFRSF1A-201T or TNFRSF1A-1135T alleles. Genetic variations in these proinflammatory mediators and their receptors appear to influence the susceptibility and severity of the inflammatory response within the eyes of patients during the development of IAU.

Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization.

Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover, and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.

Arterial carboxyhemoglobin level and outcome in critically ill patients.

OBJECTIVE: Arterial carboxyhemoglobin is elevated in patients with critical illness. It is an indicator of the endogenous production of carbon monoxide by the enzyme heme oxygenase, which modulates the response to oxidant stress. The objective was to explore the hypothesis that arterial carboxyhemoglobin level is associated with inflammation and survival in patients requiring cardiothoracic intensive care. DESIGN: Prospective, observational study. SETTING: A cardiothoracic intensive care unit. PATIENTS: All patients admitted over a 15-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial carboxyhemoglobin, bilirubin, and standard biochemical, hematologic, and physiologic markers of inflammation were measured in 1,267 patients. Associations were sought between levels of arterial carboxyhemoglobin, markers of the inflammatory response, and clinical outcome. Intensive care unit mortality was associated with lower minimum and greater maximal carboxyhemoglobin levels (p < .0001 and p < .001, respectively). After adjustment for age, gender, illness severity, and other relevant variables, a lower minimum arterial carboxyhemoglobin was associated with an increased risk of death from all causes (odds risk of death, 0.391; 95% confidence interval, 0.190-0.807; p = .011). Arterial carboxyhemoglobin correlated with markers of the inflammatory response. CONCLUSIONS: Both low minimum and high maximum levels of arterial carboxyhemoglobin were associated with increased intensive care mortality. Although the heme oxygenase system is protective, excessive induction may be deleterious. This suggests that there may be an optimal range for heme oxygenase-1 induction.

TNF polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic beryllium disease and beryllium sensitization.

BACKGROUND: Beryllium stimulates TNF-alpha from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. OBJECTIVE: We sought to relate TNF polymorphisms to beryllium-stimulated TNF-alpha production, to the development of CBD, and to the risk of more severe CBD over time. METHODS: We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-alpha production from a subset of subjects. RESULTS: Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-alpha production was significantly increased in patients with CBD compared with that seen in those only sensitized (P = .0002). Those subjects with the TNF -857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-alpha production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-alpha levels (P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao(2) at maximum exercise was noted in patients with CBD with the -1031C allele (P = .03) and with haplotypes other than the TNF haplotype 1 (P = .01), 3 (from 5) of which contain the -1031C allele. CONCLUSIONS: The -857T allele and haplotype 1 are associated with BAL cell TNF-alpha production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD. CLINICAL IMPLICATIONS: TNF promoter variants are not risk factors for CBD or sensitization.

The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma.

OBJECTIVE: Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), antitopoisomerase antibody, and anti-RNA polymerase antibody. The purpose of this study was to investigate tumor necrosis factor (TNF) polymorphisms in scleroderma, with the specific aim of determining whether TNF polymorphisms would prove to be stronger markers for ACA than class II major histocompatibility complex (MHC). METHODS: We studied 214 UK white scleroderma patients and 354 healthy controls. All subjects were investigated for 5 TNF promoter region polymorphisms by sequence-specific polymerase chain reaction. RESULTS: We showed that an NF-kappaB binding site polymorphism (known to be functionally relevant) in the TNF promoter region was present in 51.8% of patients with ACA and 16.3% of patients without ACA (chi(2) = 25.1, P = 0.000004 [corrected P = 0.00002]). Using haplotype mapping, we showed that this was a primary TNF association that could explain the previous weak links between ACA production and class II MHC alleles. In marked contrast to our ACA results, HLA class II (especially DRB1*11) appeared to be primary in that it could explain the weaker TNF association with antitopoisomerase production. Further, we observed a separate TNF haplotype to be associated with scleroderma per se, although the level of significance was much lower (chi(2) = 8.7, P = 0.003 [corrected P = 0.02]). CONCLUSION: We believe these findings may have importance both for the directional pathogenesis of scleroderma progression and for the treatment of scleroderma with anti-TNF agents.

Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis.

Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C), -863(C/A), -857(C/T), -307(G/A), and -237(G/A) in two clinically well-defined groups of white patients (British [UK] and Dutch [NL]) with sarcoidosis, each with their own control subjects. Polymorphisms were determined using SSP-PCR. A total of 772 individuals were studied (96 UK patients, 354 UK control subjects, 100 NL patients, 222 NL controls). A significant increase in the rarer TNF -857T allele was found in both sarcoidosis populations. In total 25.5% of the sarcoid patients carried the TNF -857T allele versus 14.1% of the control subjects (p = 0.003, p(c) = 0.02). In the sarcoidosis group the allele frequency of this polymorphism was 13.5% versus 7.3% in the control subjects (p = 0.0003, p(c) = 0.002). Subgroup analysis showed a significant increase in the rarer TNF -307A (TNF-2) allele in patients with Löfgren's syndrome (p = 0.006, p(c) = 0.03). Our finding does not necessarily imply that the two polymorphisms relate to different functions; it may be that one or both are in linkage disequilibrium with the causal site. This requires further studies of functionality and linkage disequilibrium.