Respiratory Tract Epithelium Research Articles

Fitness of SARS-CoV-2 Omicron subvariants in respiratory and gastrointestinal cell lines as determined by RT-ddPCR and whole genome sequencing.

The fitness of SARS-CoV-2 Omicron subvariants was determined in human epithelial and continuous cells of the respiratory and gastrointestinal tracts. Competition experiments over 4 days were performed followed by quantification of variant ratios by reverse transcription-droplet digital PCR. These quantitative data were correlated with whole genome sequencing. In competition experiments of two subvariants, the more recent XBB.1 subvariant outcompeted the BA.1.15 subvariant at early time points in the upper respiratory tract epithelium. No difference in replication was observed between the two subvariants in the lower respiratory tract. Furthermore, XBB.1 predominated over BA.1.15 and JN.1.1 subvariants in the gastrointestinal tract.

Infant-derived human nasal organoids exhibit relatively increased susceptibility, epithelial responses, and cytotoxicity during RSV infection

BackgroundRespiratory syncytial virus (RSV) causes significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe compared to healthy adults is not fully understood. MethodsWe used ex-vivo human nasal organoid platforms from infants and adults to investigate the underlying mechanism of this disease disparity at the initial site of RSV replication, the nasal epithelium. ResultsInfant-derived human nasal organoid-air liquid interface (HNO-ALIs) lines were more susceptible to early RSV replication. Moreover, infant-derived HNO-ALIs elicited a statistically significant greater overall cytokine response, enhanced mucous production, and greater cellular damage compared to their adult counterparts. Furthermore, the adult cytokine response was associated with a superior regulatory cytokine response, which could explain less cellular damage than in infant lines. ConclusionsOur data highlights substantial differences in how infant and adult upper respiratory tract epithelium responds to RSV infection at the cellular level. These differences in epithelial cellular response can lead to impaired mucociliary clearance, a more dysregulated innate immune response predisposing infants to more severe RSV infection compared to adults.

Epithelial Antimicrobial Peptide/Protein and Cytokine Expression Profiles Obtained from Nasopharyngeal Swabs of SARS-CoV-2-Infected and Non-Infected Subjects.

Immune responses of the epithelia of the upper respiratory tract are likely crucial in early inhibition of the viral replication and finally clearance of SARS-CoV-2. We aimed to compare the expression profiles of antimicrobial peptides/proteins (AMPs) and related cytokines observed in the nasopharynx of SARS-CoV-2-infected patients and non-infected controls and to assess the associations between these parameters and COVID-19 patients' outcomes. We included 45 subjects who had tested positive for SARS-CoV-2 and 22 control subjects who had tested negative for SARS-CoV-2. Biomaterial for SARS-CoV-2 detection, as well as gene and protein expression studies, was obtained from all subjects using nasopharyngeal swabs which were performed a maximum of 7 days before inclusion in the study. Univariable and multivariable statistics were performed. When compared to the controls, the mRNA expression levels of human β-defensin 1 (hBD-1), LL-37, and trappin-2 were significantly higher in specimens of nasopharyngeal swabs from COVID-19 patients. Protein expression of hBD-1 was also increased in the COVID-19 group. mRNA expression levels of interferon-ɣ (IFN-ɣ), tumor necrosis factor- ɑ (TNF-ɑ), and interleukin-6 (IL-6) measured in SARS-CoV-2-infected patients were significantly higher than those observed in the controls, which could also be confirmed in the protein levels of IFN-ɣ and IL-6. A significant correlation between mRNA and protein levels could be observed only for IL-6. Univariable analysis revealed that low IFN-ɣ mRNA levels were associated with severe/fatal outcomes. The occurrence of COVID-19 pneumonia was significantly associated with lower expression levels of IL-6 mRNA, IFN-ɣ mRNA, and TNF-ɑ mRNA. Concerning the severe/fatal outcomes, the multivariable logistic regression model revealed that none of the aforementioned parameters remained significant in the model. However, the logistic regression model revealed that higher TNF-ɑ mRNA expression was a significant independent predictor of absence of pneumonia [odds ratio: 0.35 (95% CI 0.14 to 0.88, p = 0.024)]. In conclusion, nasopharyngeal expression of AMPs (hBD-1, LL-37, and trappin-2) and cytokines (IL-6, IFN-ɣ, and TNF-ɑ) is upregulated in response to early SARS-CoV-2 infection, indicating that these AMPs and cytokines play a role in the local host defense against the virus. Upregulated nasopharyngeal TNF-ɑ mRNA expression during the early phase of SARS-CoV-2 infection was a significant independent predictor of the absence of COVID-19 pneumonia. Hence, high TNF-ɑ mRNA expression in the nasopharynx appears to be a protective factor for lung complications in COVID-19 patients.

P02-48 Beneficial effect of differently-coated Selenium Nanoparticles in 3D cell culture models mimicking the respiratory tract and intestinal epithelium

P02-48 Beneficial effect of differently-coated Selenium Nanoparticles in 3D cell culture models mimicking the respiratory tract and intestinal epithelium

Stanovenie mukociliárneho klírensu u pacientov so symptómami laryngofaryngeálneho refl uxu – preliminárne výsledky

Summary: Introduction: Mucociliary clearance represents an important protective mechanism of the respiratory tract. Results of multiple studies indicate that gastroesophageal reflux can participate in worsening mucociliary clearance leading to laryngopharyngeal reflux symptoms including recurrent upper respiratory tract infections. Thereby, we decided to provide ciliary beat frequency of the upper respiratory tract epithelium in patients with laryngopharyngeal reflux. Materials and methods: We enrolled 23 patients with laryngopharyngeal reflux symptoms. Control group consisted of 9 healthy volunteers. Patients were enrolled upon a positive questionnaire reflux symptom index (RSI >13 points), with no proton pump inhibitor treatment. We obtained a nasopharyngeal swab and evaluated ciliary beat frequency of the respiratory epithelium using highspeed videomicroscopy and special sofware Ciliary Analysis. We compared the values of ciliary beat frequency with values from healthy volunteers. Results: We provided median, minimal and maximum values of ciliary beat frequency. Median ciliary beat frequency in healthy volunteers was significantly higher than in patients with laryngopharyngeal reflux symptomatology (10.86 ± 1.67 vs. 6.6 ± 2.2; P <0.001). Maximum ciliary beat frequency was also significantly higher in healthy volunteers than in patients with LPR (17.9 ± 0.95 vs. 15.3 ± 2.39; P <0.001). Minimal value had no significant difference. Correlation analysis showed an inverse correlation between median ciliary beat frequency of the respiratory epithelium and LPR symptoms (RSI value) (P <0.04). Conclusion: Patients with laryngopharyngeal reflux symptoms had lower ciliary beat frequency compared to healthy volunteers. The degree of frequency defect correlates with the degree of their laryngopharyngeal symptoms. More studies are needed to confirm direct evidence of gastroesophageal reflux etiology in mucociliary clearance worsening. Key words: mucociliary clearance – laryngopharyngeal reflux – cilia

NRP1 antagonism as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis.

Neuropilin-1 (NRP1) is expressed on the surface epithelium of respiratory tract and immune cells, demonstrating its possible function in regulating the immune response in airway disease. However, its role in patient with chronic rhinosinusitis (CRS) remains unknown. This study aimed to elucidate the role of NRP1 in CRS with nasal polyps (CRSwNP). Sinonasal biopsy specimens were immunohistochemically stained to investigate NRP1 expression. Double immunofluorescence, immunoblotting, and real-time polymerase chain reaction were performed to evaluate NRP1 in primary human nasal epithelial cells (hNECs). An NRP1 inhibitor was administered to a murine nasal polyp (NP) model. NRP1 was highly expressed in the epithelium in patients with CRSwNP compared to nasal tissue from controls and CRS without NP patients. NRP1 and vascular endothelial growth factor were upregulated in hNECs under hypoxia. Treatment with NRP1 inhibitor (EG00229) reduced the secretion of interleukin (IL)-1β, IL-6, IL-8, and IL-33 cytokines, as well as inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin E2 in hNECs. We found that NRP1 was highly expressed in the airway epithelium in the murine NP model. The group treated with the NRP1 inhibitor had significantly fewer nasal polypoid lesions and reduced accumulations of immune cells. These findings reveal that NRP1 is upregulated in CRS and NP epithelium, and the inhibition of NRP1 may lead to a reduction in NP growth and immune cell infiltration. Our results suggest that NRP1 inhibition could be a novel possibility for treating nasal polyposis.

Equine herpesvirus type 1 (EHV-1) replication at the upper respiratory entry site is inhibited by neutralizing EHV-1-specific IgG1 and IgG4/7 mucosal antibodies.

Equine herpesvirus type 1 (EHV-1) is a contagious respiratory pathogen that infects the mucosa of the upper respiratory tract (URT). Mucosal immune responses at the URT provide the first line of defense against EHV-1 and are crucial for orchestrating immunity. To define host-pathogen interactions, we characterized B-cell responses, antibody isotype functions, and EHV-1 replication of susceptible (non-immune) and clinically protected (immune) horses after experimental EHV-1 infection. Nasal secretion and nasal wash samples were collected and used for the isolation of DNA, RNA, and mucosal antibodies. Shedding of infectious virus, EHV-1 copy numbers, viral RNA expression, and host B-cell activation in the URT were compared based on host immune status. Mucosal EHV-1-specific antibody responses were associated with EHV-1 shedding and viral RNA transcription. Finally, mucosal immunoglobulin G (IgG) and IgA isotypes were purified and tested for neutralizing capabilities. IgG1 and IgG4/7 neutralized EHV-1, while IgG3/5, IgG6, and IgA did not. Immune horses secreted high amounts of mucosal EHV-1-specific IgG4/7 antibodies and quickly upregulated B-cell pathway genes, while EHV-1 was undetected by virus isolation and PCR. RNA transcription analysis reinforced incomplete viral replication in immune horses. In contrast, complete viral replication with high viral copy numbers and shedding of infectious viruses was characteristic for non-immune horses, together with low or absent EHV-1-specific neutralizing antibodies during viral replication. These data confirm that pre-existing mucosal IgG1 and IgG4/7 and rapid B-cell activation upon EHV-1 infection are essential for virus neutralization, regulation of viral replication, and mucosal immunity against EHV-1.IMPORTANCEEquine herpesvirus type 1 (EHV-1) causes respiratory disease, abortion storms, and neurologic outbreaks known as equine herpes myeloencephalopathy (EHM). EHV-1 is transmitted with respiratory secretions by nose-to-nose contact or via fomites. The virus initially infects the epithelium of the upper respiratory tract (URT). Host-pathogen interactions and mucosal immunity at the viral entry site provide the first line of defense against the EHV-1. Robust mucosal immunity can be essential in protecting against EHV-1 and to reduce EHM outbreaks. It has previously been shown that immune horses do not establish cell-associated viremia, the prerequisite for EHM. Here, we demonstrate how mucosal antibodies can prevent the replication of EHV-1 at the epithelium of the URT and, thereby, the progression of the virus to the peripheral blood. The findings improve the mechanistic understanding of mucosal immunity against EHV-1 and can support the development of enhanced diagnostic tools, vaccines against EHM, and the management of EHV-1 outbreaks.

TAS2R38 Bitter Taste Receptor Polymorphisms in Patients with Chronic Rhinosinusitis with Nasal Polyps Preliminary Data in Polish Population.

Chronic rhinosinusitis (CRS) affects 5-12% of the general population, and the most challenging patients are those with nasal polyposis (CRSwNP). Its complexity, unpredictability, and difficulties in selecting a treatment plan individually for each patient prompted scientists to look for possible genetic causes of this disease. It was proven that single nucleotide polymorphisms (SNPs) in the TAS2R38 gene may affect the mobility and the activity of the ciliated epithelium of the upper respiratory tract what can contribute to individual differences in susceptibility to CRS. There are two common haplotypes: a "protective" type (PAV), and a "non-protective" type (AVI). CRS patients who are homozygous PAV/PAV are considered as less susceptible to the severe course of the disease, whereas patients with AVI/AVI haplotype are more vulnerable. The aim of this study was to examine TAS2R38 gene polymorphisms among CRSwNP patients and control group (N = 544) with the evaluation of the association between the distribution of studied polymorphic variants and the incidence as well as severity of CRSwNP in the study group. Whole blood samples from CRSwNP patients (N = 106) and the control group (N = 438) were analyzed for alleles of the TAS2R38 gene using real-time PCR single nucleotide polymorphism genotyping assays for rs713598, rs1726866, and rs10246939. PAV (SG: 41%; CG: 49%) and AVI (SG: 59%; CG: 51%) haplotypes were the only ones detected in the study. The AVI haplotypes were 1.5 times more frequent in the study group than in the control group (p = 0.0204; OR = 1.43). AVI/AVI individuals tended to have more severe symptoms in the VAS scale, less QoL in the SNOT-22 test, and a bigger nasal obstruction upon endoscopic examination. Patients with PAV/PAV were twice more likely to have minor changes in preoperative CT scans (p = 0.0158; OR = 2.1; Fi = 0.24). Our study confirmed that the PAV/PAV diplotype might have some protective properties and carrying the AVI haplotype might predispose to the development of CRSwNP.

Влияние барьерных методов профилактики острых респираторных вирусных инфекций на функциональное состояние назального цилиарного эпителия у детей с рецидивирующей бронхиальной обструкцией

Aim. Study effect of cellulose powder on the functional state of the ciliary epithelium in children with bronchial obstruction. Design. Open prospective non-randomized clinical study. Material and methods. The study involved 60 children from 3 to 11 years, with a history of frequent acute respiratory viral infections (ARVI), occurring with bronchial obstruction or exacerbation of bronchial asthma. Motor activity of the ciliary epithelium was registered with the digital high-speed videomicroscopy method initially and 3 months after the start of the three-month course of its application. Patients were also assessed for the frequency of acute respiratory viral infections; the objective and subjective symptoms of ARVI episodes were evaluated with a point scale during the follow-up period. Results. After completing the three-month course of cellulose powder with wild garlic extract usage, it was revealed that 55 (91.7%) children did not get ARVI during follow-up, 5 (8.3%) children had ARVI once. There was a reduction in the duration of the disease, a decrease in the severity of symptoms compared with those in previous years, on the scale of severity assessment of symptoms in patients with ARVI: in previous years — 17 (16; 18) points, when interviewed after the use of the studied drug — 9 (7; 10) points (p < 0.05). Of the five children who were ill, only one child developed obstructive bronchitis on the background of a viral infection. The relative number of cells with motile cilia: the middle nasal concha (MNC) — 25% (20%; 30%), the inferior nasal concha (INC) — 25% (15%; 30%); 3 months after the start of taking the cellulose powder: MNC — 40% (30%; 45%), INC — 35% (35%; 45%) (p < 0.01). Ciliary beat frequency in patients initially: MNC — 4.7 (4.2; 5.9) Hz, INC — 4.9 (4.2; 5.7) Hz; 3 months after MNC — 5.9 (5.7; 7.9) Hz (p < 0.01), INC — 6.2 (5.5; 7.2) Hz (р < 0.05). Conclusion. The use of cellulose powder for preventive purposes prevents infection with ARVIs, protects against reinfection, and also helps to reduce the duration and the severity of the disease manifestations. There is a positive dynamics in the functional status of the ciliary epithelium of the upper respiratory tract, which may reflect a more complete restoration of the mucosa against the background of the absence of ARVI. Keywords: ciliary epithelium, cilia, prevention of acute respiratory viral infections, children, fine cellulose powder.

Club cell protein (CC16) in serum as an effect marker for small airway epithelial damage caused by diesel exhaust and blasting fumes in potash mining

ObjectiveThe effect marker club cell protein (CC16) is secreted by the epithelium of the small respiratory tract into its lumen and passes into the blood. Increased amounts of CC16 in serum are observed during acute epithelial lung injury due to air pollutants. CC16 in serum was determined as part of this cross-sectional study in underground potash miners on acute and chronic health effects from exposures to diesel exhaust and blasting fumes.MethodsNitrogen oxides, carbon monoxide, and diesel particulate matter were measured in 672 workers at a German potash mining site on a person-by-person basis over an early shift or midday shift, together with CC16 serum concentrations before and after the respective shift. CC16 concentrations and CC16 shift-differences were evaluated with respect to personal exposure measurements and other quantitative variables by Spearman rank correlation coefficients. CC16 shift-differences were modeled using multiple linear regression. Above-ground workers as reference group were compared to the exposed underground workers.ResultsSerum concentrations of CC16 were influenced by personal characteristics such as age, smoking status, and renal function. Moreover, they showed a circadian rhythm. While no statistically significant effects of work-related exposure on CC16 concentrations were seen in never smokers, such effects were evident in current smokers.ConclusionThe small airways of current smokers appeared to be vulnerable to the combination of measured work-related exposures and individual exposure to smoking. Therefore, as health protection of smokers exposed to diesel exhaust and blasting fumes, smoking cessation is strongly recommended.

Mathematical Modeling of the Lethal Synergism of Coinfecting Pathogens in Respiratory Viral Infections: A Review.

Influenza A virus (IAV) infections represent a substantial global health challenge and are often accompanied by coinfections involving secondary viruses or bacteria, resulting in increased morbidity and mortality. The clinical impact of coinfections remains poorly understood, with conflicting findings regarding fatality. Isolating the impact of each pathogen and mechanisms of pathogen synergy during coinfections is challenging and further complicated by host and pathogen variability and experimental conditions. Factors such as cytokine dysregulation, immune cell function alterations, mucociliary dysfunction, and changes to the respiratory tract epithelium have been identified as contributors to increased lethality. The relative significance of these factors depends on variables such as pathogen types, infection timing, sequence, and inoculum size. Mathematical biological modeling can play a pivotal role in shedding light on the mechanisms of coinfections. Mathematical modeling enables the quantification of aspects of the intra-host immune response that are difficult to assess experimentally. In this narrative review, we highlight important mechanisms of IAV coinfection with bacterial and viral pathogens and survey mathematical models of coinfection and the insights gained from them. We discuss current challenges and limitations facing coinfection modeling, as well as current trends and future directions toward a complete understanding of coinfection using mathematical modeling and computer simulation.

CALU-3 lung cells three-dimensionally assembled onto CellFate® matrix present angiotensin-converting enzyme-2 activity.

Currently, there is a great need for the development of three-dimensional (3D) in vitro lung models. Particularly, the production of a suitable 3D model of pulmonary epithelium for understanding the pathophysiology of diseases such as the COVID-19 must consider the tissue architecture and presence, for example, of the angiotensin-converting enzyme-2 (ACE-2) in the cells. Different polymeric membranes are being used to support cell culturing, especially of lung cells, however, there is still no information about the culture of these cells onto bacterial nanocellulose (BNC) matrices. We have used the BNC matrix CellFate® as a support for the assembly of a 3D in vitro model of lung epithelium, composed of human lung fibroblasts (HLF) and lung adenocarcinoma cells (CALU-3). CellFate® matrices were made from bacterial fermentation resulting in a natural and biocompatible biopolymer. Cells were cultured onto CellFate® and maintained in a 5% CO2 humidified atmosphere at 37°C. Cell viability was assessed by the resazurin method The samples were, then, exposed to the air-liquid interface (ALI), and histologically analyzed. ACE-2 activity was verified on the hydrolyze of the fluorogenic substrate Mca-APK(Dnp)-OH, and its presence was evaluated by flow cytometry. The expression of the anionic transporter SLCO3A1 was evaluated by qPCR. Cell viability analysis indicates that CellFate® was not toxic to these cells. By flow cytometry, the presence of the ACE-2 was identified in the CALU-3 cells surface corroborating the results obtained from enzymatic activity analysis. The SLCO3A1 transporter expression was identified in cells cultured onto CellFate®, but not in cells cultured onto the transwell (control). CALU-3 cells cultivated onto CellFate® resulted in a pseudostratified organization, a typical morphology of the human respiratory tract epithelium. The current model opens perspectives for studies involving physiological characterization, improving its relevance for the understanding of the pathophysiology of diseases as well as the response to drugs.

Using of herbal mucolytics in the complex therapy of acute and chronic rhinosinusitis

Chronic rhinosinusitis is a polyetiological heterogeneous disease that is characterized by inflammation of the nasal mucosa and paranasal sinuses. The clinical picture of this pathology may include nasal congestion and rhinorrhea. Studies on the pathogenesis of chronic rhinosinusitis have yielded insufficient results, however, a number of factors that predispose to the development of this disease are currently identified according to clinical guidelines. Among these are both anatomical anomalies and some chronic diseases (rhinitis, atopy), immune system disorders (immunodeficiencies), etc. Mucoactive drugs are used in the treatment of acute and chronic rhinosinusitis to restore the transport function of the upper respiratory tract epithelium. Their mechanism of action is aimed at restoring mucociliary clearance. This therapy also affects the viscous discharge, which is produced during rhinosinusitis and accumulates in the paranasal sinuses and nasal cavity, worsening the course of the inflammatory process. Specialists distinguish the following forms of mucoactive drugs: mucolytics, mucokinetics and mucoregulators. The article considers the aspects of the clinical use of herbal mucolytics for the treatment of acute and chronic rhinosinusitis, in the pathogenesis of which the nasal mucosa edema plays a key role. The authors summarise the most conclusive evidence to date on the need to use herbal mucolytics in the complex therapy of acute and chronic rhinosinusitis. The modern topical therapy of acute and chronic rhinosinusitis in the otorhinolaryngology practice is presented. Herbal medicinal products have a proven secretolytic and anti-inflammatory effect, accelerate the relief of symptoms and reduce the recovery time of patients. The clinical guidelines recommend to prescribe these drugs in addition to the complex therapy of rhinosinusitis to patients suffering from ARS and CRS, who has no contraindications.

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

Analysis of Nipah Virus Replication and Host Proteome Response Patterns in Differentiated Porcine Airway Epithelial Cells Cultured at the Air-Liquid Interface.

Respiratory tract epithelium infection plays a primary role in Nipah virus (NiV) pathogenesis and transmission. Knowledge about infection dynamics and host responses to NiV infection in respiratory tract epithelia is scarce. Studies in non-differentiated primary respiratory tract cells or cell lines indicate insufficient interferon (IFN) responses. However, studies are lacking in the determination of complex host response patterns in differentiated respiratory tract epithelia for the understanding of NiV replication and spread in swine. Here we characterized infection and spread of NiV in differentiated primary porcine bronchial epithelial cells (PBEC) cultivated at the air-liquid interface (ALI). After the initial infection of only a few apical cells, lateral spread for 12 days with epithelium disruption was observed without releasing substantial amounts of infectious virus from the apical or basal sides. Deep time course proteomics revealed pronounced upregulation of genes related to type I/II IFN, immunoproteasomal subunits, transporter associated with antigen processing (TAP)-mediated peptide transport, and major histocompatibility complex (MHC) I antigen presentation. Spliceosomal factors were downregulated. We propose a model in which NiV replication in PBEC is slowed by a potent and broad type I/II IFN host response with conversion from 26S proteasomes to immunoproteasomal antigen processing and improved MHC I presentation for adaptive immunity priming. NiV induced cytopathic effects could reflect the focal release of cell-associated NiV, which may contribute to efficient airborne viral spread between pigs.

Assessment of immunomodulation and regulation of cell cycle in epithelium and stroma after Cidofovir injection in patients with recurrent respiratory papillomatosis-Pilot study.

Recurrent respiratory papillomatosis is strictly connected with human papillomavirus (HPV) infection of the epithelium of the upper respiratory tract. The main treatment of lesions located in the larynx or lower pharynx includes microsurgical excision by using aCO2 laser. To decrease the amount of surgical procedures gain in importance combined therapy with antiviral agents. The aim of this study was to investigate the effect of the intralesional application of Cidofovir on the tissue of laryngeal papillomas. We have shown that simultaneous microsurgery with adjuvant therapy of Cidofovir reduces chronic inflammation (by measuring the expression of CD4 and CD8 in tissue samples), cell proliferation, and regulates the cell cycle of HPV-infected cells by reducing the expression of p53 and p63 proteins. In addition, this strategy reduces the multiple surgical procedures and regrowth of the pathology.

Effective antibiotic therapy for community-acquired otorhinolaryngological respiratory infection (clinical description)

The State Report on the state of sanitary and epidemiological well-being of the population in the Russian Federation speaks of the continued growth of respiratory infections, reaching more than 33 million cases and amounting to more than 606 billion rubles of direct economic damage in 2021. Of particular importance is the new coronavirus infection SARS-CoV-2, and manifestations of its various new genovariants, for example, variant B.1.1.529 called omicron, causes various inflammatory nosologies on the part of the mucous membranes of the ENT organs (acute rhinosinusitis, acute tonsillopharyngitis, acute otitis media). The viral agent, damaging the epithelium of the upper respiratory tract, creates favorable conditions for the activation of the microbial flora. Identification of a respiratory agent is most often carried out only in severe cases of the disease, so the basic diagnosis is based on clinical symptoms. The relevance of studying the rational use of antibacterial drugs in the treatment of community-acquired respiratory infections in practical otorhinolaryngology is associated not only with the frequency of occurrence, but with a high risk of complications. As a rule, antibacterial drugs are actively used in the complex therapy of acute bacterial etiology of the upper respiratory tract. Due to the high variability and increasing antibiotic resistance, antimicrobial agents are not always rationally used for outpatients. In this context, as noted in the clinical guidelines, one of the topical issues is the rational dosed use of antibacterial drugs in accordance with the pharmacokinetics, pharmacodynamics and efficacy of prescribing a cephalosporin antibiotic in the form of dispersible tablets in the treatment of patients with acute inflammatory diseases of the upper respiratory tract and ear, as an example, clinical cases.

Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19.

The recent outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China has spread rapidly around the world, leading to a widespread and urgent effort to develop and use comprehensive approaches in the treatment of COVID-19. While oral therapy is accepted as an effective and simple method, since the primary site of infection and disease progression of COVID-19 is mainly through the lungs, inhaled drug delivery directly to the lungs may be the most appropriate route of administration. To prevent or treat primary SARS-CoV-2 infections, it is essential to target the virus port of entry in the respiratory tract and airway epithelium, which requires rapid and high-intensity inhibition or control of viral entry or replication. To achieve success in this field, inhalation therapy is the most attractive treatment approach due to efficacy/safety profiles. In this review article, pulmonary drug delivery as a unique treatment option in lung diseases will be briefly reviewed. Then, possible inhalation therapies for the treatment of symptoms of COVID-19 will be discussed and the results of clinical trials will be presented. By pulmonary delivery of the currently approved drugs for COVID-19, efficacy of the treatment would be improved along with reducing systemic side effects.Graphical abstract

Programmed Host Cell Death and Infectious Process of Mycoplasma

A common characteristic of Mycoplasma diseases is their chronicity, Mycoplasma spp. infection have been frequently associated with upper respiratory infections, chronic lung disease , asthma, meningeal encephalitis, mastitis, arthritis, heart problems, sterility, bone problems , oviduct dysfunctions and death in human and different animal species. In former years, changeable expression of membrane antigens has been detected in a number of Mycoplasma spp., resulting in the assumption that immune prevarication may be an important part of the their infection and pathogenesis. It has been determined how the attachment organelle, which mediates the complicated interactions between various adhesins and auxiliary adhesion proteins to mediate the critical first stage of cytoadherence to respiratory tract epithelium. Additionally, it has been demonstrated that inflammatory cytokines cause tissue damage by intracellular localization, direct cytotoxicity, and activation of the inflammatory cascade via Toll-like receptors (TLRs), and inflammosome activation, which causes air passage inflammation. All of these play crucial roles in the infectious process. This paper seeks to provide a thorough assessment of recent developments in our understanding of Mycoplasma pathogenesis with the understanding of its virulence mechanisms.

Non-typeable Haemophilus influenzae airways infection: the next treatable trait in asthma?

Asthma is a complex, heterogeneous condition that affects over 350 million people globally. It is characterised by bronchial hyperreactivity and airways inflammation. A subset display marked airway neutrophilia, associated with worse lung function, higher morbidity and poor response to treatment. In these individuals, recent metagenomic studies have identified persistent bacterial infection, particularly with non-encapsulated strains of the Gram-negative bacterium Haemophilus influenzae. Here we review knowledge of non-typeable H. influenzae (NTHi) in the microbiology of asthma, the immune consequences of mucosal NTHi infection, various immune evasion mechanisms, and the clinical implications of NTHi infection for phenotyping and targeted therapies in neutrophilic asthma. Airway neutrophilia is associated with production of neutrophil chemokines and proinflammatory cytokines in the airways, including interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-17A and tumour necrosis factor. NTHi adheres to and invades the lower respiratory tract epithelium, inducing the NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes. NTHi reduces expression of tight-junction proteins, impairing epithelial integrity, and can persist intracellularly. NTHi interacts with rhinoviruses synergistically via upregulation of intracellular cell adhesion molecule 1 and promotion of a neutrophilic environment, to which NTHi is adapted. We highlight the clinical relevance of this emerging pathogen and its relevance for the efficacy of long-term macrolide therapy in airways diseases, we identify important unanswered questions and we propose future directions for research.