Mitochondrial genetic background plays a role in increasing risk to asthma

A number of studies suggest that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To shed light for the first time on the role of the mitochondrial genome in the etiology of asthma we analyzed the mitochondrial tRNA genes and part of their flanking regions in patients with asthma compared with a set of healthy controls. We found a total of 10 mutations in 56 out of 76 asthmatic patients. Four of these mutations were not found in the control group, five were observed at a significantly lower frequency in controls, but none of the combinations of mutations detected in asthma patients was observed in the controls. Furthermore, we observed that 27.6% of the asthma patients (vs. 4% of the controls) belonged to the haplogroup U (Fisher test P = 0.00) and a positive significant correlation was found between the occurrence of the haplogroup U and the severity of the disease (Fisher test P = 0.02). Whereas further studies in larger cohorts are needed to confirm these observations we suggest that the mitochondrial genetic background plays a key role in asthma development.     

Letters to the Editor

The following is the abstract of the article discussed in thesubsequent letter:

Verbanck, S., D. Schuermans, A. Van Muylem, M. Paiva, M. Noppen, and W. Vincken. Ventilation distribution duringhistamine provocation. J. Appl. Physiol.83(6):1907-1916, 1997.We investigated ventilation inhomogeneityduring provocation with inhaled histamine in 20 asymptomatic nonsmokingsubjects. We used N₂ multiple-breath washout (MBW) toderive parameters S_cond andS_acin as a measurement of ventilationinhomogeneity in conductive and acinar zones of the lungs,respectively. A 20% decrease of forced expiratory volume in 1 s(FEV₁) was used to distinguish responders fromnonresponders. In the responder group, average FEV₁decreased by 26%, whereas S_cond increased by390% with no significant change in S_acin. In the nonresponder group, FEV₁ decreased by 11%, whereasS_cond increased by 198% with no significantS_acin change. Despite the absence of change inS_acin during provocation, baselineS_acin was significantly larger in the respondervs. the nonresponder group. The main findings of our study are thatduring provocation large ventilation inhomogeneities occur, that thesmall airways affected by the provocation process are situated proximalto the acinar zone where the diffusion front stands, and that, inaddition to overall decrease in airway caliber, there is inhomogeneousnarrowing of parallel airways.

     

Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study

Sarcoidosis is considered as a disorder of protracted immune response to an as yet unidentified causative agent that leads to granuloma formation. Material from M. tuberculosis and P. acne has been repeatedly detected in the sarcoidosis lesions, implying the involvement of the Toll-like receptor2 (TLR2) gene that responds to these intracellular pathogens. Since TLR2 association studies have produced controversial results, we sought to investigate whether the downstream signalling molecule MyD88 could be linked to disease susceptibility. We analyzed a total of 93 cases with sarcoidosis and of 89 controls for the most common MyD88 SNPs: ?938C>A (rs4988453) and 1944C>G (rs4988457). There is evidence that the genotype distributions of both variants are associated with the development of sarcoidosis (p = 0.038 for ?938C>A and p = 0.026 for 1944C>G). In particular, ?938A and 1944G carriers were associated with risk of sarcoidosis [OR = 2.48 (1.23–5.02) and OR = 0.33 (0.14–0.76)], respectively, indicating dominance of the mutant alleles; however, the adjustment of the effect size for age and sex diminished the significance. The haplotype analysis showed association for the ?938A/1944G haplotype (p < 0.001). Since genetic association studies have linked MyD88 to Hodgkin’s lymphoma it is tempting to speculate that MyD88 may contribute to the granuloma formation that characterizes sarcoidosis.     

Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma

Overexpression of AQP1 has recently been shown to be an independent prognostic factor in pleural mesothelioma favoring survival. This paper presents a data mining and bioinformatics approach towards the evaluation of the gene expression profile of AQP1 in malignant pleural mesothelioma and of AQP1 associated markers in the context of mesothelioma disease phenotype, CDKN2A gene deletion, sex and asbestos exposure. The data generated were thus again subjected to differential expression profile analysis. Here we report that AQP1 is overexpressed in epithelioid mesothelioma and identify TRIP6 and EFEMP2 as candidate genes for further investigation in mesothelioma.     

Insulin NO-dependent action on airways smooth muscles.

In order to find out how insulin acts on airway smooth muscle and which mechanisms could be involved, we studied the effect of insulin on contraction induced, first, by KCl and, second, by Acetylcholine (Ach), before and after epithelium removal, and finally in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor. Tracheal smooth muscle strips from 24 rabbits, 6 being used for each experiment. Each muscle strip was pretreated with a solution containing either 80 mM KCl or 10(-5) Ach and increasing doses of insulin (range 10(-10)--10(-5) M) in the presence or absence of 10(-4) M L-NAME. A reference curve for contraction evoked by 80 mM KCl or 10(-5) M Ach in the presence or absence of 10(-4) M L-NAME was recorded each time before the pretreatment mentioned above. Insulin evoked a concentration-dependent inhibition of tracheal smooth muscle contraction, induced by 80 mM KCl or 10(-5) M Ach. After epithelium removal, insulin (10(-8), 10(-7) M) evoked statistically significant increases to the contractions induced by 10(-5) M Ach compared to the contractions induced by 10(-5) M Ach and insulin in the presence of epithelium (P < 0.05). These increases were higher when 10(-4) M l-NAME was added to the bath (P < 0.05). In conclusion, these results indicate that insulin inhibits tracheal smooth muscle contraction by acting on epithelium and releasing NO.     

Effects of SNP, ouabain, and amiloride on electrical potential profile of isolated sheep pleura.

The fluid and solute transport properties of pleural tissue were studied by using specimens of intact visceral and parietal pleura from adult sheep lungs. The samples were transferred to the laboratory in a Krebs-Ringer solution at 4 degrees C within 1 h from the death of the animal. The pleura was then mounted as a planar sheet in a Ussing-type chamber. The results that are presented in this study are the means of six different experiments. The spontaneous potential difference and the inhibitory effects of sodium nitroprusside (SNP), ouabain, and amiloride on transepithelial electrical resistance (R(TE)) were measured. The spontaneous potential difference across parietal pleura was 0.5 +/- 0.1 mV, whereas that across visceral pleura was 0.4 +/- 0.1 mV. R(TE) of both pleura was very low: 22.02 +/- 4.1 Omega. cm2 for visceral pleura and 22.02 +/- 3.5 Omega. cm2 for parietal pleura. There was an increase in the R(TE) when SNP was added to the serosal bathing solution of parietal pleura and to the serosal or mucosal bathing solution in visceral pleura. The same was observed when ouabain was added to the mucosal surface of visceral pleura and to either the mucosal or serosal surface of parietal pleura. Furthermore, there was an increase in R(TE) when amiloride was added to the serosal bathing solution of parietal pleura. Consequently, the sheep pleura appears to play a role in the fluid and solute transport between the pleural capillaries and the pleural space. There results suggest that there is a Na+ and K+ transport across both the visceral and parietal pleura.     

Airway responsiveness: role of inflammation, epithelium damage and smooth muscle tension

The purpose of this study was the effect of epithelium damage on mechanical responses of airway smooth muscles under different resting tension. We performed acetylcholine (ACh) (10(-5) M)-induced contraction on tracheal strips from 30 rabbits in five groups (0.5, 1, 1.5, 2 and 2.5 g) before and after epithelium removal. At low resting tension (0.5-1.5 g), the epithelium removal decreased the ACh-induced contractions. At 2 g resting tension, the epithelium removal increased the ACh-induced contractions of airways with intact epithelium about 20%. At 2.5 g resting tension, the elevation of contraction is about 25% (P<0.01). Consequently, after epithelium loss, the resting tension determines the airway smooth muscles responsiveness. In asthma, mediators such as ACh act on already contracted inflammatory airways, which results in additional increase of contraction. In contrast, low resting tension, a condition that simulates normal tidal breathing, protects from bronchoconstriction even when the epithelium is damaged.     

Rapid effects of 17beta-estradiol and progesterone on sheep visceral and parietal pleurae via a nitric oxide pathway.

We investigated the effects of 17beta-estradiol and progesterone on transepithelial electrical resistance (R(TE)) in sheep visceral and parietal pleurae. Specimens of intact pleurae from adult female sheep were used. The samples were transferred to the laboratory within 30 min after death of the animal in a Krebs-Ringer solution at 4 degrees C. The pleura was then mounted as a planar sheet in Ussing-type chambers, and electrical measurements were made. There was an increase in R(TE) in all of the samples examined after addition of 17beta-estradiol and progesterone in visceral and parietal pleurae. This increase was rapid within 1 min, lasted for ~15 min, returned to the basal level within 30-45 min, and was dose dependent. Tamoxifen, an estrogen receptor antagonist, did not significantly eliminate the effect of 17beta-estradiol. Furthermore, no steroid receptors were identified in cytosolic preparations of visceral and parietal pleura with ligand binding assays. The estrogen- and progesterone-induced increase in R(TE) in both visceral and parietal pleurae was affected by addition of an inhibitor of nitric oxide synthase. Indeed, previous administration of N(omega)-nitro-L-arginine methyl ester prevented the increase in R(TE) by 17beta-estradiol and progesterone. These results suggest that 17beta-estradiol and progesterone induce an increase in R(TE) in both visceral and parietal pleura and thus alter the transepithelial permeability. The effect of steroids may be accounted for by rapid release of nitric oxide in pleura.     

Body composition in severe refractory asthma: comparison with COPD patients and healthy smokers

Background

Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated.

Methodology and Principal Findings

213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3–18.3)–19.5(18.4–21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I–III COPD and comparable to those of stage IV COPD patients [18.0(17.3–18.3)–18.8(17.8–20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used.

Conclusions and Significance

SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies.