Human airway trypsin-like protease, a serine protease involved in respiratory diseases.

More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment, or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity, and regulation, including the expression profile of HAT, and discuss its possible roles in respiratory physiology and disease.

Interactions of GST Polymorphisms in Air Pollution Exposure and Respiratory Diseases and Allergies.

PURPOSE OF REVIEW: The purpose of this review is to summarize the evidence from recently published original studies investigating how glutathione S-transferase (GST) gene polymorphisms modify the impact of air pollution on asthma, allergic diseases, and lung function. RECENT FINDINGS: Current studies in epidemiological and controlled human experiments found evidence to suggest that GSTs modify the impact of air pollution exposure on respiratory diseases and allergies. Of the nine articles included in this review, all except one identified at least one significant interaction with at least one of glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 1 (GSTM1), or glutathione S-transferase theta 1 (GSTT1) genes and air pollution exposure. The findings of these studies, however, are markedly different. This difference can be partially explained by regional variation in the exposure levels and oxidative potential of different pollutants and by other interactions involving a number of unaccounted environment exposures and multiple genes. Although there is evidence of an interaction between GST genes and air pollution exposure for the risk of respiratory disease and allergies, results are not concordant. Further investigations are needed to explore the reasons behind the discordancy.

Janus kinase inhibition prevents cancer- and myocardial infarction-mediated diaphragm muscle weakness in mice.

Respiratory dysfunction is prevalent in critically ill patients and can lead to adverse clinical outcomes, including respiratory failure and increased mortality. Respiratory muscles, which normally sustain respiration through inspiratory muscle contractions, become weakened during critical illness, and recent studies suggest that respiratory muscle weakness is related to systemic inflammation. Here, we investigate the pathophysiological role of the inflammatory JAK1/3 signaling pathway in diaphragm weakness in two distinct experimental models of critical illness. In the first experiment, mice received subcutaneous injections of PBS or C26 cancer cells and were fed chow formulated with or without the JAK1/3 inhibitor R548 for 26 days. Diaphragm specific force was significantly reduced in tumor-bearing mice receiving standard chow; however, treatment with the JAK1/3 inhibitor completely prevented diaphragm weakness. Diaphragm cross-sectional area was diminished by ∼25% in tumor-bearing mice but was similar to healthy mice in tumor-bearing animals treated with R548. In the second study, mice received sham surgery or coronary artery ligation, leading to myocardial infarction (MI), and were treated with R548 or vehicle 1 h postsurgery, and once daily for 3 days. Diaphragm specific force was comparable between sham surgery/vehicle, sham surgery/R548 and MI/R548 groups, but significantly decreased in the MI/vehicle group. Markers of oxidative damage and activated caspase-3, mechanisms previously identified to reduce muscle contractility, were not elevated in diaphragm extracts. These experiments implicate JAK1/3 signaling in cancer- and MI-mediated diaphragm weakness in mice, and provide a compelling case for further investigation.

Ciliopathies: Does HDAC6 Represent a New Therapeutic Target?

Cilia are cellular appendages with critical roles in sensing and transducing environmental signals and guiding fluid flow. Consistent with these diverse activities, defects in ciliary structure or function have been implicated in a variety of human diseases, collectively known as 'ciliopathies'. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes through its deacetylase and ubiquitin-binding activities. There is accumulating evidence that HDAC6 is a major driver of ciliary disassembly. Small-molecule compounds that inhibit HDAC6 have been demonstrated to restore ciliary structure and function in several different ciliopathies. Here, we discuss recent findings that highlight the important role for HDAC6 in mediating ciliary disassembly and the potential for HDAC6-selective inhibitors as therapeutics for specific ciliopathies.

UGT1A1*28 Genotypes and Respiratory Disease in Very Preterm Infants: A Cohort Study.

BACKGROUND: Respiratory disease in the very preterm infant is frequent and often severe. Bilirubin is both a potent neurotoxin and antioxidant, and may have a clinical impact on preterm respiratory disease. The Gilbert genotype, the UGT1A1*28 allele, is the major known genetic cause of variation in bilirubin. OBJECTIVES: To study the association between respiratory disease in the very preterm infant and the UGT1A1*28 allele. METHODS: This is a cohort study of 1,354 very preterm infants (gestational age <32 weeks) born in Jutland, Denmark in 1997-2011. Genotypes were obtained from the Danish Neonatal Screening Biobank, and clinical information was obtained from the databases of two tertiary neonatal intensive care units. Outcomes were the need for surfactant therapy, any need for and duration of supplementary oxygen and bronchopulmonary dysplasia (BPD). RESULTS: Per UGT1A1*28 allele, odds were increased for any need of supplementary oxygen (odds ratio 1.26; 1.05-1.50) and for BPD (odds ratio 1.71; 1.23-2.39), the need of supplementary oxygen increased by 6.38 days (1.87-10.89), and chance per day of no longer needing supplementary oxygen was reduced (hazard rate 0.84; 0.76-0.93). No effect was observed for need of surfactant treatment (odds ratio 1.08; 0.91-1.28). Hardy-Weinberg equilibrium was unlikely for the cohort (p < 0.012). This could be explained by death prior to genotype sampling. In tests of robustness this failed to explain the primary results. CONCLUSIONS: Compared to the common genotype, UGT1A1*28 genotypes were associated with an increased need of oxygen supplementation and risk of BPD in very preterm newborns.

The occurrence of neonatal acute respiratory disorders in 21-hydroxylase deficiency.

Patients with 21-hydroxyase deficiency (21-OHD) usually do not present clinical symptoms other than female ambiguous genitalia and skin pigmentation at birth. However, we have found a case of neonatal transient tachypnea with spontaneous pneumomediastinum in a neonate with 21-OHD at birth. The purpose of this study was to investigate the occurrence of neonatal respiratory disorders in 21-OHD patients. From April 1989 to March 2009, 478,337 Japanese newborns were screened for congenital adrenal hyperplasia in Niigata prefecture. Among these newborns, 26 patients were diagnosed as having 21-OHD. We investigated the presence of neonatal respiratory disorders based on the retrospective medical records of 24 full-term patients with 21-OHD. Three of the 24 patients (12.5%) had neonatal acute respiratory disorders. Neonatal transient tachypnea developed in all patients with only oxygenation for two or three days after birth. Chest X-rays showed spontaneous pneumothorax or pneumomediastinum in two patients. In conclusion, 21-OHD patients may present with acute respiratory disorders, especially transient tachypnea with spontaneous pneumothorax, at birth. In cases of delivering mothers having other children with 21-OHD, newborns require attention regarding neonatal respiratory disorders if a prenatal diagnosis has not been performed.

[Theophylline, a new look to an old drug]. / Teofilina, una nueva mirada a un medicamento antiguo.

OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC-2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma.

Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast.

Phosphodiesterase-4 (PDE4) is an important cAMP-metabolising enzyme in immune and inflammatory cells, airway smooth muscle and pulmonary nerves. The phosphodiesterase 4 (PDE4) enzyme plays a significant role in modulating the activity of cAMP, an important second messenger that mediates the relaxation of airway smooth muscle and suppresses inflammatory cell function, thereby attenuating the inflammatory response. Selective inhibitors of this enzyme show a broad spectrum of activity in animal models of COPD and asthma. These drugs block the hydrolysis of cAMP via inhibition of PDE4 and are attractive candidates for novel anti-inflammatory drugs. At present, two second-generation PDE4 inhibitors for the treatment of COPD and asthma patients are being tested in clinical Phase III trials. The most advanced compound is the orally active, selective PDE4 inhibitor cilomilast (Ariflo, SB-207499, cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]-cyclohexanecarboxylic acid; GlaxoSmithKline). Cilomilast shows high selectivity for cAMP-specific PDE4, an isoenzyme that predominates in pro-inflammatory and immune cells and that is 10-fold more selective for PDE4D than for PDE4A, -B or -C. In vitro, cilomilast suppresses the activity of several pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD. Moreover, it is highly active in animal models of these diseases. Cilomilast has been shown to exert potent anti-inflammatory effects both in vitro and in vivo. It is orally active and may be effective in the treatment of asthma and COPD; however, complete assessment of the therapeutic value of this novel compound class must await the outcome of longer-term clinical trials. This review presents a summary of the preclinical and clinical profile of cilomilast in patients with COPD.

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease.

Respiratory diseases pose a multifaceted dilemma. Although the symptoms and pathology are obvious and provide multiple opportunities for therapeutic investigation, at the same time, the molecular complexities and prioritisation are overwhelming. Even within a disease such as asthma, the number of inducers, cell types, secondary mediators, chemical changes, immune responses and tissue modifications is remarkable. One means of therapeutically targeting this complexity is to identify individual factors responsible for regulating multiple disease processes. The mitogen-activated protein kinase family integrates multiple diverse stimuli, and, in turn, initiates a cell response by phosphorylating and thereby modulating the activity of many target proteins. The c-Jun N-terminal kinase is a critical regulator of pro-inflammatory genes, tissue remodelling and apoptosis, and, therefore, represents an attractive target for novel therapies. Pre-clinical and clinical investigation into the efficacy of c-Jun N-terminal kinase inhibitors has been ongoing since the late 1990s. Over the course of this work, hypotheses have shifted as to the role of c-Jun N-terminal kinase in the many processes that promote allergic, inflammatory, obstructive and fibrotic diseases of the lung. Inhibition of c-Jun N-terminal kinase may indeed provide a means of suppressing more pathological mechanisms in respiratory disease than first suspected.

Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of respiratory disease.

Asthma and chronic obstructive pulmonary disease (COPD) are two of the most common chronic diseases worldwide, yet the classes of drug licensed to treat these conditions have not changed appreciably over the last 20 years. Inhaled bronchodilators and glucocorticosteroids (often in combination) form the mainstay of therapy for respiratory diseases, but many patients (including the elderly and children) can have problems using inhaler devices and there is a clear preference for oral therapy. The prevalence of these respiratory diseases is on the increase worldwide and continues to represent an area of medicine with unmet medical needs, particularly in the treatment of COPD. Despite this increase, very few new classes of drugs have been introduced into clinical practice. Phosphodiesterase-4 inhibitors are a novel class of drugs in development for the treatment of respiratory diseases and there are a number of lead compounds in late clinical development. This review focuses on one of the most promising drugs in development, roflumilast, which has undergone extensive clinical evaluation.

Reduced expression of neuropeptides can be related to respiratory disturbances in Rett syndrome.

We immunohistochemically examined neurotransmitter systems, which function in the brainstem and are involved in neuronal organization of respiration, in an autopsy brain from a patient with Rett syndrome (RS). Immunoreactivity (IR) for tyrosine hydroxylase, a functional marker for catecholaminergic neurons, was severely reduced in the locus ceruleus, while that for tryptophan hydroxylase involved in serotonin synthesis was spared in the raphe nuclei. In the brainstem, IR for substance P (SP) was reduced in the parabrachial complex and that for methionine-enkephalin (met-enk) was affected in the parabrachial, hypoglossal, dorsal vagal and solitary nuclei. In addition, expressions of these neuropeptides were also disturbed in the basal ganglia. A widespread altered expression of antagonistic neuropeptides, SP and met-enk, may be involved in the pathogenesis of RS, especially in its respiratory manifestation.

Clinical and analytical studies of sheep dosed with various preparations of Astragalus lusitanicus.

Dosing different preparations and extracts of Astragalus lusitanicus to lambs showed the fresh plant or its dry powder were highly toxic while the ethyl acetate or methanol extract did not cause toxicosis, suggesting the toxic principle is an extremely water soluble compound. The animals alternated excitement and depression, with cardiac and respiratory disorders terminally. Alpha-mannosidase inhibition was not detected in blood of dosed lambs, but an inhibitory activity was in tissues from lambs given the fresh plant or its powder. There was increased aspartate aminotransferase and creatine kinase activity, suggesting skeletal muscle and neurological effects. Thin-layer chromatography and the alpha-mannosidase inhibition assay did not detect swainsonine in ethyl acetate, methanol or water: methanol plant extracts.

[Bioluminescent determination of NAD- and NADP-dependent lymphocytic glutamate dehydrogenases]. / Bioliuminestsentnoe opredelenie aktivnosti NAD- i NADF-zavisimykh glutamatdegidrogenas limoftsitov.

A sensitive bioluminescent rapid method for estimating the activity of pyridine nucleotide-(phosphate)-dependent glutamate dehydrogenases (NAD(P)-GDH) of human peripheral blood lymphocytes is suggested. 10000 cells is sufficient per analysis, up to 100 measurements may be made within 3 hrs. Normal subjects and subjects often suffering from acute respiratory diseases were examined for the aforesaid parameter. The findings evidence the diagnostic significance of NAD(P)-GDH for the detection of subjects at risk of developing acute respiratory diseases.