Mathias Holm

Carbon dioxide mediates duodenal mucosal alkaline secretion in response to luminal acidity in the anesthetized rat

BACKGROUND & AIMS Acid exposure of the duodenum elicits various functional responses, e.g., an increased mucosal alkaline secretion. Despite low pH in luminal contents, the mucosal secretion of bicarbonate-rich fluid results in pH neutrality at the surface epithelium. It follows that it is probably not luminal pH that triggers the secretory response. The present study was undertaken to investigate if CO2 could serve as an intermediate messenger between luminal acid and the mucosal secretory response. METHODS Experiments were performed on chloralose-anesthetized rats. The duodenal mucosal alkaline secretion was measured by in situ pH-stat titration. RESULTS Exposure of the duodenal mucosa to CO2, administered either as a pregassed solution (pH 4, PCO2 700 mm Hg) or as an acidified bicarbonate solution (pH 6.4, PCO2 240 mm Hg), raised the alkaline output by approximately 65%. This response was blocked by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (0.3 mmol/L intraluminally) but not by indomethacin (5 mg/kg intravenously). CONCLUSIONS Exposure of the duodenal mucosa to solutions with high concentrations of CO2 increases the mucosal alkaline secretion despite an almost neutral pH. Data indicate that the L-arginine/NO pathway is involved in the mediation of this response.

Sympathetic and renin-angiotensin activation during graded hypovolemia in pigs: impact on mesenteric perfusion and duodenal mucosal function.

Sympathetic and angiotensinergic activation reduce splanchnic oxygen delivery during hypovolemia, which may lead to failure of the intestinal mucosal barrier and eventually multiple organ dysfunction. This study integrates sympathetic and angiotensinergic responses with splanchnic hemody-namics and duodenal mucosal function during hypovolemia and evaluates pharmacologic blockade of either system to ameliorate the impact of acute hypovolemia. Chloralose-anesthetized pigs subjected to 20 and 40% blood volume reductions were randomized to controls or administered guanethidine or enalaprilate to block sympathetic and angiotensinergic activation, as assessed by plasma norepinephrine spillover and angiotensin II levels, respectively. Mesenteric and hepatic oxygen delivery/consumption as well as duodenal mucosal alkaline secretion and potential difference were determined. Hypovolemia preferentially increased mesenteric sympathetic outflow and caused a vigorous angiotensinergic activation. Guanethidine and enalaprilate blocked effectively the sympathetic and angiotensinergic responses. Treatment with enalaprilate, but not guanethidine, prevented the reduction of mesenteric oxygenation and duodenal mucosal alkaline secretion and potential difference observed in control animals. The down-regulation of mesenteric oxygenation and duodenal mucosal function during hypovolemia can be prevented by administration of enalaprilate, whereas guanethidine is uneffective in this respect. Interference with the renin-angiotensin system might be of clinical interest to support mesenteric perfusion and organ function in hypovolemia.

Occupational Exposure and New-onset Asthma in a Population-based Study in Northern Europe (RHINE)

Objectives: In a large population-based study among adults in northern Europe the relation between occupational exposure and new-onset asthma was studied. Methods: The study comprised 13 284 subjects born between 1945 and 1973, who answered a questionnaire 1989–1992 and again 1999–2001. Asthma was defined as ‘Asthma diagnosed by a physician’ with reported year of diagnose. Hazard ratios (HR), for new-onset adult asthma during 1980–2000, were calculated using a modified job-exposure matrix as well as high-risk occupations in Cox regression models. The analyses were made separately for men and women and were also stratified for atopy. Results: During the observation period there were 429 subjects with new-onset asthma with an asthma incidence of 1.3 cases per 1000 person-years for men and 2.4 for women. A significant increase in new-onset asthma was seen for men exposed to plant-associated antigens (HR = 3.6; 95% CI [confidence interval] = 1.4–9.0), epoxy (HR = 2.4; 95% CI = 1.3–4.5), diisocyanates (HR = 2.1; 95% CI = 1.2–3.7) and accidental peak exposures to irritants (HR = 2.4; 95% CI = 1.3–4.7). Both men and women exposed to cleaning agents had an increased asthma risk. When stratifying for atopy an increased asthma risk were seen in non-atopic men exposed to acrylates (HR = 3.3; 95% CI = 1.4–7.5), epoxy compounds (HR = 3.6; 95% CI = 1.6–7.9), diisocyanates and accidental peak exposures to irritants (HR = 3.0; 95% CI = 1.2–7.2). Population attributable risk for occupational asthma was 14% for men and 7% for women. Conclusions: This population-based study showed that men exposed to epoxy, diisocyanates and acrylates had an increased risk of new-onset asthma. Non-atopics seemed to be at higher risk than atopics, except for exposure to high molecular weight agents. Increased asthma risks among cleaners, spray painters, plumbers, and hairdressers were confirmed.

The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated rat duodenal mucosal alkaline secretion

BackgroundThis study investigates bradykinin and nitric oxide as potential mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion. Duodenal mucosal alkaline secretion was measured in methohexital- and α-chloralose-anaesthetised rats by means of in situ pH-stat titration. Immunohistochemistry and Western blot were used to identify the BK2 receptors.ResultsThe AT2 receptor agonist CGP42112A (0.1 μg kg-1 min-1) administered intravenously increased the duodenal mucosal alkaline secretion by ~50 %. This increase was sensitive to the selective BK2 receptor blocker HOE140 (100 ng/kg iv), but not to luminal administration of the NOS blocker L-NAME (0.3 mM). Mean arterial pressure did not differ between groups during the procedures. Immunohistochemistry showed a distinct staining of the crypt epithelium and a moderate staining of basal cytoplasm in villus enterocytes.ConclusionThe results suggest that the AT2-receptor-stimulated alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal mucosal epithelium.

The angiotensin II receptor type 2 agonist CGP 42112A stimulates NO production in the porcine jejunal mucosa

BackgroundThis study was conducted to elucidate if nitric oxide is released by the porcine jejunal mucosa upon selective stimulation of AT2 receptors and the possible involvement of iNOS, and to investigate the presence of jejunal AT1 and AT2 receptors. Young landrace pigs were anaesthetized with ketamine and α-chloralose. Jejunal luminal NO output was assessed by intraluminal tonometry and analysed by chemiluminescense. Western blot analysis quantified mucosal iNOS and detected AT1 and AT2 receptor protein expression. AT1 and AT2 receptor RNA expression was detected by rtPCR.ResultsBaseline luminal NO output correlated significantly to baseline mucosal iNOS-protein content. In animals treated with the AT2-receptor agonist CGP42112A (n = 11) luminal NO output increased significantly (at 0.1 micrograms kg-1 min-1 and 1.0 micrograms kg-1 min-1), but not in animals simultaneously treated with the AT2-receptor antagonist PD123319 (bolus 0.3 mgkg-1, infusion 0.03 mg kg-1 h-1) (n = 7). No differences in iNOS protein expression were found between groups or before/after the administration of drugs. Western blot and rtPCR recognised expression of the AT1 and AT2 receptors in jejunal tissue.ConclusionThe results suggest that activation of AT2 receptors increases jejunal luminal NO output. This response was not due to an increase in the expression of the iNOS protein in the mucosa.

DYNAMIC INVOLVEMENT OF THE INDUCIBLE TYPE OF NITRIC OXIDE SYNTHASE IN ACID-INDUCED DUODENAL MUCOSAL ALKALINE SECRETION IN THE RAT

It has previously been shown that mucosal nitric oxide synthase (NOS) is involved in acid-induced duodenal mucosal alkaline secretion. The primary aim of the present study was to elucidate which isoform of NOS is responsible in rats. Immunohistochemistry showed that inducible NOS (iNOS) was constitutively expressed in villous epithelial cells. Exposing the duodenal mucosa to 10 mM HCl resulted in an increased duodenal mucosal alkaline secretion. This response was totally inhibited by intraluminal administration of a selective inhibitor of iNOS (l-N6-1-iminoethyl-lysine). One hour after the acid exposure, western blot technique showed a marked increase in mucosal iNOS expression. A second acid exposure resulted in a further stimulation of alkaline secretion. These data suggest that exposure of the duodenal mucosa to HCl initiates an increased mucosal alkaline secretion, via NO synthesis mediated by iNOS located in the epithelial cells of the villi. In addition, luminal acid stimulates expression of iNOS.

The Urban-Rural Gradient In Asthma: A Population-Based Study in Northern Europe.

The early life environment appears to have a persistent impact on asthma risk. We hypothesize that environmental factors related to rural life mediate lower asthma prevalence in rural populations, and aimed to investigate an urban-rural gradient, assessed by place of upbringing, for asthma. The population-based Respiratory Health In Northern Europe (RHINE) study includes subjects from Denmark, Norway, Sweden, Iceland and Estonia born 1945–1973. The present analysis encompasses questionnaire data on 11,123 RHINE subjects. Six categories of place of upbringing were defined: farm with livestock, farm without livestock, village in rural area, small town, city suburb and inner city. The association of place of upbringing with asthma onset was analysed with Cox regression adjusted for relevant confounders. Subjects growing up on livestock farms had less asthma (8%) than subjects growing up in inner cities (11%) (hazard ratio 0.72 95% CI 0.57–0.91), and a significant urban-rural gradient was observed across six urbanisation levels (p = 0.02). An urban-rural gradient was only evident among women, smokers and for late-onset asthma. Analyses on wheeze and place of upbringing revealed similar results. In conclusion, this study suggests a protective effect of livestock farm upbringing on asthma development and an urban-rural gradient in a Northern European population.

Menstrual cycle and respiratory symptoms in a general Nordic-Baltic population.

RATIONALE There is little knowledge of variations in respiratory symptoms during the menstrual cycle in a general population, and potential modifying factors are not investigated. OBJECTIVES To investigate menstrual cycle variation in respiratory symptoms in a large general population, using chronobiology methodology, and stratifying by body mass index (BMI), smoking, and asthma status. METHODS A total of 3,926 women with regular cycles less than or equal to 28 days and not taking exogenous sex hormones answered a postal questionnaire regarding the first day of their last menstruation and respiratory symptoms in the last 3 days. Moving 4-day means were computed to smooth uneven records of daily sampling; best-fitting 28-day composite cosine curves were applied to each time series to describe rhythmicity. MEASUREMENTS AND MAIN RESULTS Significant rhythmic variations over the menstrual cycle were found in each symptom for all subjects and subgroups. Wheezing was higher on cycle Days 10-22, with a midcycle dip near the time of putative ovulation (approximately Days 14-16) in most subgroups. Shortness of breath was higher on days 7-21, with a dip just before midcycle in many subgroups. Cough was higher just after putative ovulation for subjects with asthma, BMI greater than or equal to 23 kg/m(2), and smokers, or just before ovulation and menses onset for low symptomatic subgroups. CONCLUSIONS Respiratory symptoms varied significantly during the menstrual cycle and were most frequent from the midluteal to midfollicular stages, often with a dip near the time of ovulation. The patterns varied by BMI, smoking, and asthma status. These relations link respiratory symptoms with hormonal changes through the menstrual cycle and imply a potential for individualized chronotherapy for respiratory diseases.

Respiratory health in cleaners in Northern Europe : is susceptibility established in early life?

Rationale There is some evidence that maternal smoking increases susceptibility to personal smoking’s detrimental effects. One might question whether early life disadvantage might influence susceptibility to occupational exposure. Objectives In this cross-sectional study we investigated respiratory symptoms, asthma and self-reported chronic obstructive pulmonary disease (COPD) as related to working as a cleaner in Northern European populations, and whether early life factors influenced susceptibility to occupational cleaning’s unhealthy effects. Methods The RHINE III questionnaire study assessed occupational cleaning in 13,499 participants. Associations with respiratory symptoms, asthma and self-reported COPD were analysed with multiple logistic regressions, adjusting for sex, age, smoking, educational level, parent´s educational level, BMI and participating centre. Interaction of occupational cleaning with early life disadvantage (maternal smoking, severe respiratory infection <5 years, born during winter months, maternal age at birth >35 years) was investigated. Main Results Among 2138 ever-cleaners the risks of wheeze (OR 1.4, 95% CI 1.3–1.6), adult-onset asthma (1.5 [1.2–1.8]) and self-reported COPD (1.7 [1.3–2.2]) were increased. The risk increased with years in occupational cleaning (adult-onset asthma: ≤1 year 0.9 [0.7–1.3]; 1–4 years 1.5 [1.1–2.0]; ≥4 years 1.6 [1.2–2.1]). The association of wheeze with cleaning activity ≥4 years was significantly stronger for those with early life disadvantage than in those without (1.8 [1.5–2.3] vs. 1.3 [0.96–1.8]; pinteraction 0.035). Conclusions Occupational cleaners had increased risk of asthma and self-reported COPD. Respiratory symptom risk was particularly increased in persons with factors suggestive of early life disadvantage. We hypothesize that early life disadvantage may increase airway vulnerability to harmful exposure from cleaning agents later in life.

Menopause Is Associated with Accelerated Lung Function Decline.

Rationale: Menopause is associated with changes in sex hormones, which affect immunity, inflammation, and osteoporosis and may impair lung function. Lung function decline has not previously been investigated in relation to menopause. Objectives: To study whether lung function decline, assessed by FVC and FEV1, is accelerated in women who undergo menopause. Methods: The population‐based longitudinal European Community Respiratory Health Survey provided serum samples, spirometry, and questionnaire data about respiratory and reproductive health from three study waves (n = 1,438). We measured follicle‐stimulating hormone and luteinizing hormone and added information on menstrual patterns to determine menopausal status using latent class analysis. Associations with lung function decline were investigated using linear mixed effects models, adjusting for age, height, weight, pack‐years, current smoking, age at completed full‐time education, spirometer, and including study center as random effect. Measurements and Main Results: Menopausal status was associated with accelerated lung function decline. The adjusted mean FVC decline was increased by −10.2 ml/yr (95% confidence interval [CI], −13.1 to −7.2) in transitional women and −12.5 ml/yr (95% CI, −16.2 to −8.9) in post‐menopausal women, compared with women menstruating regularly. The adjusted mean FEV1 decline increased by −3.8 ml/yr (95% CI, −6.3 to −2.9) in transitional women and −5.2 ml/yr (95% CI, −8.3 to −2.0) in post‐menopausal women. Conclusions: Lung function declined more rapidly among transitional and post‐menopausal women, in particular for FVC, beyond the expected age change. Clinicians should be aware that respiratory health often deteriorates during reproductive aging.