Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of the IL‐1 signaling pathway

Mucus plugging constitutes a nutrient‐rich nidus for a bacterial infection that has long been recognized as a potent stimulus for neutrophilic airway inflammation driving progressive lung damage in people with cystic fibrosis (CF). However, mucus plugging and neutrophilic inflammation are already present in many infants and young children with CF even in the absence of detectable bacterial infection. A series of observational studies in young children with CF, as well as investigations in animal models with CF‐like lung disease support the concept that mucus plugging per se can trigger inflammation before the onset of airways infection. Here we review emerging evidence suggesting that activation of the interleukin‐1 (IL‐1) signaling pathway by hypoxic epithelial cell necrosis, leading to the release of IL‐1α in mucus‐obstructed airways, may be an important mechanistic link between mucus plugging and sterile airway inflammation in early CF lung disease. Furthermore, we discuss recent data from preclinical studies demonstrating that treatment with the IL‐1 receptor (IL‐1R) antagonist anakinra has anti‐inflammatory as well as mucus modulating effects in mice with CF‐like lung disease and primary cultures of human CF airway epithelia. Collectively, these studies support an important role of the IL‐1 signaling pathway in sterile neutrophilic inflammation and mucus hypersecretion and suggest inhibition of this pathway as a promising anti‐inflammatory strategy in patients with CF and potentially other muco‐obstructive lung diseases.     

Seroepidemiology of hepatitis A infection in India: changing pattern.

OBJECTIVE: Recent changes in the epidemiology of hepatitis A virus (HAV) infection and the availability of effective vaccines have renewed interest in this infection. We determined the age-related prevalence of anti-HAV antibodies in India and looked for differences by known risk factors for HAV infection. METHODS: In this prospective study, serum samples obtained from 1612 subjects aged 1 to 60 at six centers in five cities (Calcutta, Cochin, Indore, Jaipur and Patna) during the period February to August 1998 were tested for anti-HAV antibodies. Demographic and socio-economic information was obtained by questionnaire. RESULTS: The overall seroprevalence rate was 65.9%, varying from 26.2% to 85.3% in various cities; there was no difference between males and females. Seropositivity increased with age from 52.2% in the 1-5 year age group to 80.8% in those aged 16 years or more. Seroprevalence rates were significantly lower in those aged 1-5 years compared with other age groups (p<0.0001). There was no difference in seroprevalence between those with monthly family income Rs 5001. Multivariate analysis showed that anti-HAV seroprevalence varied significantly by source of water supply, being highest when the supply was municipal. CONCLUSION: Our results indicate an epidemiological pattern of intermediate endemicity. This finding has public health implications as it indicates that a significant proportion of the Indian adolescent and adult population is at risk of HAV infection.     

Koronarthrombosen und -ektasien nach langj?hriger Einnahme von anabolen Steroiden

Summary. Chronic abuse of anabolic steroids is widespread. Hypertrophy of skeletal and heart muscle is a well-known effect of chronic anabolic steroid abuse. Structural alterations of blood vessels are new side effects. We report a case of a 32-year-old bodybuilder after long-term use of anabolic steroids who died of cardiac arrest. Coronary angiography and autopsy findings showed espacially a hypertrophic heart, structural changes of coronary arteries, intracoronary thrombosis and myocardial infarction, ventricular thrombosis and systemic embolism Zusammenfassung. Die Einnahme anaboler Steroide zur Leistungssteigerung und Vermehrung der Muskelmasse ist bei Kraftsportlern und Bodybuildern weit verbreitet. Neben ihrer anabolen Wirkung auf die Skelett- und Herzmuskulatur sind strukturelle Veränderungen an Blutgefäßen selten beschrieben. Wir berichten über einen 32-jährigen Bodybuilder, der nach langjähriger Einnahme anaboler Steroide strukturelle Veränderungen an Koronararterien entwickelte und an den Folgen rezidivierender linksventrikulärer Infarkte verstarb.     

Substitutions in the eyelet region disrupt cefepime diffusion through the Escherichia coli OmpF channel

The Escherichia coli OmpF porin is a nonspecific channel involved in the membrane translocation of small hydrophilic molecules and especially in the passage of beta-lactam antibiotics. In order to understand the dynamic of charged-compound uptake through bacterial porins, specific charges located in the E. coli OmpF channel were mutated. Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size. These charge alterations located in the constriction area have differential effects on cephalosporin diffusion and substantially modify the profile of antibiotic susceptibility.     

The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways.

Cystic fibrosis (CF) airway cells, besides their well-known defect in cAMP-dependent Cl- conductance, are characterized by an enhanced Na+ conductance. In this study we have examined the Na+ conductance in human respiratory tract by measuring transepithelial voltage and resistance (Vte, Rte) and by assessing membrane voltages (Vm) of freshly isolated airway epithelial cells from CF and non-CF patients. Basal amiloride inhibitable (10 micromol/liter) equivalent short circuit current (Isc = Vte/Rte) was significantly increased in CF compared with non-CF tissues. After stimulation by forskolin (10 micromol/liter) a significant depolarization of Vm corresponding to the cAMP-dependent activation of a Cl- conductance was observed in non-CF but not in CF airway cells. In non-CF tissue but not in CF tissue the effects of amiloride and N-methyl-D-glucamine on Vm were attenuated in the presence of forskolin. Also the amiloride-inhibitable Isc was significantly reduced by forskolin (1 micromol/liter) and isobutylmethylxanthine (IBMX; 100 micromol/liter) only in non-CF tissue. We conclude that cystic fibrosis transmembrane conductance regulator acts as a downregulator of epithelial Na+ channels in human airways. This downregulation of epithelial Na+ channels is absent in CF airways, leading to hyperabsorption and to the characteristic increase in mucus viscosity.     

Pharmacotherapy of the Ion Transport Defect in Cystic Fibrosis

Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na⁺ absorption, mediated by epithelial Na⁺ channels (ENaC), and deficient Cl^? transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO₃ ^? secretion. In other epithelial tissues, epithelial Na⁺ conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl^? channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl^? channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways.In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y₂ receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na⁺ absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca²⁺-dependent Cl^? channel is activated that may compensate for the CFTR Cl^? channel defect. Thus activation of P2Y₂ receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y₂ receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na⁺ transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.