Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases.

N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders.

Effects of Green Tea Polyphenol Epigallocatechin-3-Gallate on Markers of Inflammation and Fibrosis in a Rat Model of Pulmonary Silicosis.

Inhalation of silica particles causes inflammatory changes leading to fibrotizing silicosis. Considering a lack of effective therapy, and a growing information on the wide actions of green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), the aim of this study was to evaluate the early effects of EGCG on markers of inflammation and lung fibrosis in silicotic rats. The silicosis model was induced by a single transoral intratracheal instillation of silica (50 mg/mL/animal), while controls received an equivalent volume of saline. The treatment with intraperitoneal EGCG (20 mg/kg, or saline in controls) was initiated the next day after silica instillation and was given twice a week. Animals were euthanized 14 or 28 days after the treatment onset, and the total and differential counts of leukocytes in the blood and bronchoalveolar lavage fluid (BALF), wet/dry lung weight ratio, and markers of inflammation, oxidative stress, and fibrosis in the lung were determined. The presence of collagen and smooth muscle mass in the walls of bronchioles and lung vessels was investigated immunohistochemically. Early treatment with EGCG showed some potential to alleviate inflammation, and a trend to decrease oxidative stress-induced changes, including apoptosis, and a prevention of fibrotic changes in the bronchioles and pulmonary vessels. However, further investigations should be undertaken to elucidate the effects of EGCG in the lung silicosis model in more detail. In addition, because of insufficient data from EGCG delivery in silicosis, the positive and eventual adverse effects of this herbal compound should be carefully studied before any preventive use or therapy with EGCG may be recommended.

Green Tea Polyphenol (-)-Epigallocatechin-3-Gallate (EGCG): A Time for a New Player in the Treatment of Respiratory Diseases?

(-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol of green tea that possesses a wide variety of actions. EGCG acts as a strong antioxidant which effectively scavenges reactive oxygen species (ROS), inhibits pro-oxidant enzymes including NADPH oxidase, activates antioxidant systems including superoxide dismutase, catalase, or glutathione, and reduces abundant production of nitric oxide metabolites by inducible nitric oxide synthase. ECGC also exerts potent anti-inflammatory, anti-fibrotic, pro-apoptotic, anti-tumorous, and metabolic effects via modulation of a variety of intracellular signaling cascades. Based on this knowledge, the use of EGCG could be of benefit in respiratory diseases with acute or chronic inflammatory, oxidative, and fibrotizing processes in their pathogenesis. This article reviews current information on the biological effects of EGCG in those respiratory diseases or animal models in which EGCG has been administered, i.e., acute respiratory distress syndrome, respiratory infections, COVID-19, bronchial asthma, chronic obstructive pulmonary disease, lung fibrosis, silicosis, lung cancer, pulmonary hypertension, and lung embolism, and critically discusses effectiveness of EGCG administration in these respiratory disorders. For this review, articles in English language from the PubMed database were used.

Therapeutic Effects of Green Tea Polyphenol (‒)-Epigallocatechin-3-Gallate (EGCG) in Relation to Molecular Pathways Controlling Inflammation, Oxidative Stress, and Apoptosis.

(‒)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. Thanks to multiple interactions with cell surface receptors, intracellular signaling pathways, and nuclear transcription factors, EGCG possesses a wide variety of anti-inflammatory, antioxidant, antifibrotic, anti-remodelation, and tissue-protective properties which may be useful in the treatment of various diseases, particularly in cancer, and neurological, cardiovascular, respiratory, and metabolic disorders. This article reviews current information on the biological effects of EGCG in the above-mentioned disorders in relation to molecular pathways controlling inflammation, oxidative stress, and cell apoptosis.

Establishment of PANDA - a new human pancreatic ductal adenocarcinoma cell line with 3D cell culture technology.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of malignancy with one of the worst prognoses amongst any type of cancer. Surgery is applicable only to the limited number of patients with locally resectable tumors and currently represents the only curative treatment option. Treatment with chemotherapy and radiotherapy can only extend patient survival. Despite advances in conventional therapies, the five-year survival of PDAC remained largely unchanged. New in vitro and in vivo models are therefore urgently needed to investigate this type of cancer. Here, we present the establishment and characterization of a novel pancreatic cancer cell line, isolated from a patient with PDAC. Cell line abbreviated as PANDA (PANncreatic Ductal Adenocarcinoma) was established with an optimized 3D culture protocol published previously by our group. The new cancer cell line "PANDA" represents a novel in vitro approach for PDAC cancer research and new therapy testing.

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.

Metabolomic characterisation of progression and spontaneous regression of melanoma in the melanoma-bearing Libechov minipig model.

Melanoma-bearing Libechov minipig (MeLiM) represents a large animal model for melanoma research. This model shows a high incidence of complete spontaneous regression of melanoma - a phenomenon uncommon in humans. Here, we present the first metabolomic characterisation of the MeLiM model comparing animals with progressing and spontaneously regressing melanomas. Plasma samples of 19 minipigs with progression and 27 minipigs with evidence of regression were analysed by a targeted metabolomic assay based on mass spectrometry detection. Differences in plasma metabolomics patterns were investigated by univariate and multivariate statistical analyses. Overall, 185 metabolites were quantified in each plasma sample. Significantly altered metabolomic profile was found, and 42 features were differentially regulated in plasma. Besides, the machine learning approach was used to create a predictive model utilising Arg/Orn and Arg/ADMA ratios to discriminate minipigs with progressive disease development from minipigs with regression evidence. Our results suggest that progression of melanoma in the MeLiM model is associated with alteration of arginine, glycerophospholipid and acylcarnitines metabolism. Moreover, this study provides targeted metabolomics characterisation of an animal model of melanoma with progression and spontaneous regression of tumours.

Respiratory Cilia as a Therapeutic Target of Phosphodiesterase Inhibitors.

Mucociliary clearance is an essential airway defense mechanism dependent predominantly on the proper ciliary function and mucus rheology. The crucial role of cilia is evident in `a variety of respiratory diseases, as the ciliary dysfunction is associated with a progressive decline in lung function over time. The activity of cilia is under supervision of multiple physiological regulators, including second messengers. Their role is to enable a movement in coordinated metachronal waves at certain beat frequency. Ciliary function can be modulated by various stimuli, including agents from the group of beta2 agonists, cholinergic drugs, and adenosine triphosphate (ATP). They trigger cilia to move faster in response to elevated cytoplasmic Ca2+ originated from intracellular sources or replenished from extracellular space. Well-known cilia-stimulatory effect of Ca2+ ions can be abolished or even reversed by modulating the phosphodiesterase (PDE)-mediated breakdown of cyclic adenosine monophosphate (cAMP) since the overall change in ciliary beating has been dependent on the balance between Ca2+ ions and cAMP. Moreover, in chronic respiratory diseases, high ATP levels may contribute to cAMP hydrolysis and thus to a decrease in the ciliary beat frequency (CBF). The role of PDE inhibitors in airway cilia-driven transport may help in prevention of progressive loss of pulmonary function often observed despite current therapy. Furthermore, administration of selective PDE inhibitors by inhalation lowers the risk of their systemic effects. Based on this review we may conclude that selective (PDE1, PDE4) or dual PDE inhibitors (PDE3/4) increase the intracellular level of cyclic nucleotides in airway epithelial cells and thus may be an important target in the development of new inhaled mucokinetic agents. Further research is required to provide evidence of their effectiveness and feasibility regarding their cilia-modulating properties.

Phosphodiesterase inhibitors: Potential role in the respiratory distress of neonates.

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the hydrolysis of phosphodiester bonds of 3',5' cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDEs control hydrolysis of cyclic nucleotides in many cells and tissues. Inhibition of PDEs by selective or nonselective PDE inhibitors represents an effective targeted strategy for the treatment of various diseases including respiratory disorders. Recent data have demonstrated that PDE inhibitors can also be of benefit in respiratory distress in neonates. This article outlines the pharmacological properties of nonselective and selective PDE inhibitors and provides up-to-date information regarding their use in experimental models of neonatal respiratory distress as well as in clinical studies.

An unusual case of anesthetic abuse by a full-face gas mask.

The authors report a case of sniffing of halothane (Narcotan) by a 32-year-old man, master of pharmacy, through the military full-face gas mask. The liquid halothane had been applied on the scrubber of the gas mask and voluntarily inhaled. The sniffer was found dead in his flat, with the gas mask still fixed and sealed on his face. Because the authors have not encountered any report of such a case in the literature, they present and discuss this case in this article.

Pharmacologic modulation of experimentally induced allergic asthma.

Allergic asthma is the most frequent disease of the respiratory tract. The aim of the current experimental and clinical studies was to find new sources of drugs able to control asthmatic inflammation and airway hyperresponsiveness. Our experimental studies were focused on efficiency evaluation of substances able to influence activities of ion channels, phosphodiesterase (PDE) isoforms, substances from the group of polyphenols and NO metabolism modulators during experimentally induced allergic asthma.