Inflammatory Respiratory Diseases Research Articles

Assessment of Serum Metabolism and Eicosanoid Profiling in Pediatric Asthma and Bronchiolitis via Liquid Chromatography-Mass Spectrometry.

Asthma, a prevalent chronic inflammatory respiratory disease among children, was the focus of this study. Serum metabolism profiles were examined in patients diagnosed with both asthma and bronchiolitis by using ultra-high performance liquid chromatography-mass spectrometry. In this study, the serum samples from three distinct groups-comprising patients diagnosed with asthma, bronchiolitis, and a healthy control group-underwent comprehensive non-targeted metabolomics analysis and targeted eicosanoid profiling. Through both univariate and multivariate analyses, significant associations were observed between the pathophysiology of both asthma and bronchiolitis and aberrations in the metabolism of polyunsaturated fatty acids, amino acids, purines, and pathways involving cyclooxygenases and lipoxygenases, indicative of inflammatory processes and immune responses. Furthermore, metabolic changes in phosphatidylethanolamine, saturated and monounsaturated fatty acids, and bile acids were observed in the asthma group. Bronchiolitis was distinguished by disruptions in acyl carnitine and phosphatidylcholine metabolism. This study offers a new perspective on understanding the interplay of pathogenic mechanisms underlying both asthma and bronchiolitis. Its findings are significant for enhancing the diagnostic and therapeutic strategies tailored to asthma stemming from bronchiolitis.

Multiomics and experimental approaches reveal the anti-acute lung injury effects of Fallopia aubertii (L. Henry) Holub extract via IL-17/NF-κB pathway inhibition

Ethnopharmacological relevanceFallopia aubertii (L. Henry) Holub (F. aubertii), a traditional Tibetan medicine, is used in China for treating respiratory inflammatory diseases, including acute lung injury (ALI). However, the chemical constituents of F. aubertii and its anti-inflammatory mechanisms in the lungs remain poorly understood. Aim of the studyThis study aimed to identify the chemical constituents of the F. aubertii extract (FAE), evaluate its effectiveness in reducing ALI in mice, and elucidate the underlying mechanisms of its action. Materials and methodsThe chemical composition of FAE was determined using UPLC-LTQ Velos Pro-Orbitrap Elite. Network pharmacology was employed to predict the mechanisms by which FAE might mitigate ALI. Mice were administered FAE orally for seven days, followed by intratracheal instillation of lipopolysaccharide (LPS) to induce ALI. On the final day, the mice were euthanized, and their lungs were collected for transcriptome analysis, proteomics, pharmacodynamic evaluation, and mechanistic studies. Hematoxylin and eosin (H&E) staining assessed lung pathology. Transcriptome and proteomic analyses, along with real-time quantitative PCR (RT-qPCR) and western blotting, were used to investigate FAE's effects on lung inflammation and related signaling pathways. In vitro experiments further explored the anti-ALI mechanisms of FAE. Immunofluorescence assays in RAW264.7 cells examined the nuclear translocation of NF-κB. ResultsFifty-one compounds were identified in FAE, predominantly flavonoid glycosides. Network pharmacology suggested that FAE may inhibit ALI by modulating the NF-κB pathway and Th17 differentiation. RNA-seq analysis indicated that FAE might suppress inflammation through the IL-17 signaling pathway, with these findings corroborated by mRNA level measurements in vivo and in vitro. FAE alleviated LPS-induced ALI by modulating the IL-17A signaling pathway, which was confirmed through proteomic analysis. Western blotting revealed that FAE reduced the expression of IL-17A, Act1, TRAF6, and p-NF-κB, while immunofluorescence assays showed FAE inhibited LPS-induced NF-κB nuclear translocation. ConclusionFAE attenuates inflammation-mediated ALI by inhibiting the IL-17A/NF-κB signaling pathway. This study highlights the anti-ALI effects of FAE and provides a theoretical foundation for its potential use in ALI treatment.

Pyroptosis in asthma: inflammatory phenotypes, immune and non-immune cells, and novel treatment approaches.

Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed.

Wide possibilities of topical therapy in the treatment of patients with infectious and inflammatory diseases of the pharynx

Despite medical advances, infectious and inflammatory upper respiratory diseases are the most common groups of diseases among outpatients. Viruses induce acute respiratory diseases in most patients; however, bacterial and “atypical” pathogens can cause exacerbations of chronic diseases such as adenoiditis, tonsillitis, pharyngitis and others. Prescribing etiotropic drugs to patients with infectious and inflammatory diseases of the pharynx can reduce the effectiveness of the therapy due to the growth of antimicrobial resistance. Increasing etiotropic drug resistance of some pathogens requires the selection of alternative agents for patients with infectious and inflammatory diseases of the pharynx. The non-specific prophylaxis of the latter is aimed to activate inner defense mechanisms using bacterial lysates (BL). Based on a review of the literature, the article discusses the features of the use and clinical effectiveness of topical BL in infectious and inflammatory diseases of the pharynx. BL are an important supplementation to the standard therapy regimen for inflammatory upper respiratory diseases, which contributes to the restoration of the immune response autoregulation, a reliable decrease in the frequency and duration of acute forms and exacerbations of chronic upper respiratory diseases, and reduced use of antibiotics and antipyretics. Evidence of possible mechanisms to correct immunity in infectious and inflammatory diseases of the pharynx, as well as a review of the clinical effectiveness of the medicine was demonstrated by example of Imudon. Its beneficial use to treat disease in the acute period is associated with its focal action on the infectious and inflammatory lesions. The drug is effective at any stage of the disease and can be used for prophylactic purposes due to activation of mucosal immunity in the respiratory tract. The high efficiency of Imudon is determined by its ability to activate phagocytosis and production of specific immunoglobulins by plasma cells, which reduces the risk of relapses and chronicity of the disease.

The essential oils from Asarum sieboldii Miq. Alleviate allergic rhinitis by regulating tight junction and inflammation; Network analysis and preclinical validation

Ethnopharmacological relevanceEssential oils from herbs, including those from Asarum sieboldii Miq., are readily absorbed through mucous membranes, explaining their widespread use in inhalation formulations. Asarum sieboldii Miq. has a long history of traditional use for various medicinal purposes, attributed to its anti-inflammatory, antiallergic, and antioxidant properties. Despite research on Asarum sieboldii Miq. for allergic inflammation in respiratory diseases, detailed mechanistic studies are still lacking. Aim of the studyWe utilized bioinformatics and network pharmacology to identify the effectiveness of Asarum sieboldii Miq. in treating allergic rhinitis (AR). Our aim is to elucidate the potential therapeutic effects of essential oil derived from Asarum sieboldii Miq. (ASO), which is recognized for its diverse pharmacological properties, on AR. Materials and methodsCommon genes associated with the active compounds of ASO and AR were utilized to construct a related network and predict their mode of action. AR was induced in BALB/c mice by exposing them to ovalbumin (OVA) and particulate matter 10 (PM10; airborne particles <10 μm). With induction, aerosolized ASO (0.0002% and 0.02%) were administered via nebulizer for 5 min per day, three times a week for 7 weeks. Mice were examined for histopathological changes in the nasal tissue, nasal epithelial inflammation, the production of allergen-specific cytokine response in vitro and in vivo. ResultsThe common genes of ASO and AR were predicted to include 'Tight junction', 'Apoptosis', and 'TGF-beta signaling', which are the main pathways of pathogenesis in AR. Consistent with network prediction, nebulized ASO treatment effectively improved the expression of tight junction-related factors, zonula occludens-1, claudin-1, occludin and junction adhesion molecule A, in OVA + PM10 induced mice. Additionally, it reduced hyperplasia of nasal epithelial thickness, goblet cell counts, and inflammatory cell infiltration (eosinophils, neutrophils, macrophages, and lymphocytes) in nasal lavage fluid, while also alleviating allergic symptoms such as sneezing, rubbing, and serum IgE level when compared to the AR-induced group. The levels of mRNA and protein expression related to tight junctions were restored to normal levels by ASO, as confirmed in immunofluorescence analysis in nasal epithelial cells RPMI2650. Furthermore, treatment of ASO on PM10-treated nasal epithelial cells significantly reduced ROS production, recovered mitochondria membrane potential, and inhibition of the production of proinflammatory cytokines (TNF-α, IL-4, and IL-13) and inflammatory mediators linked to the MAPK/NF-κB signaling pathways. ConclusionIntranasal nebulization of ASO improves TJs and alleviates allergic nasal inflammation in AR. It supports the potential pharmaceutical application of ASO treatment for AR.

Effect of COVID-19 vaccination on the risk of developing post-COVID conditions: The VENUS study

IntroductionPost-COVID-19 conditions have emerged as a global health challenge. This study examined the long-term effects of COVID-19 vaccination on the incidence and risk of post-COVID-19 conditions in Japan. MethodsThis retrospective cohort study was conducted using a database comprising medical claims, COVID-19 case information, and vaccination records of persons residing in four Japanese municipalities. The cohort included COVID-19 cases diagnosed between August 2020 and December 2022. Participants were classified according to the duration between their most recent COVID-19 vaccination and COVID-19 occurrence (≥365 days, 150–364 days, and 14–149 days). The incidences of 36 post-COVID-19 conditions were monitored for 3, 5, and 8 months after infection. Cox proportional hazards models were used to calculate the risk of developing each post-COVID-19 condition within 8 months after infection according to vaccination status. ResultsFrom among 84,464 participants, 9642 (11.4 %) developed post-COVID-19 conditions over 8 months. The 8-month risks of developing 28 (including various respiratory conditions, cardiovascular conditions, inflammatory and immune diseases, physical conditions, psychiatric conditions, and endocrine disorders) of the 36 target conditions were significantly lower when individuals had been recently vaccinated (14–149 days) before infection. ConclusionsCOVID-19 vaccination can reduce the incidence and risk of post-COVID-19 conditions if administered within 5 months before infection. Despite having the highest mean age and prevalence of comorbidities, individuals who were most recently vaccinated had a lower risk of developing post-COVID-19 conditions. These results provide important evidence for future COVID-19 vaccination strategies.

Lysimachia mauritiana Lam. Extract Alleviates Airway Inflammation Induced by Particulate Matter Plus Diesel Exhaust Particles in Mice.

The respiratory-protective effects of Lysimachia mauritiana (LM) against airway inflammation were evaluated in a mouse model exposed to a fine dust mixture of diesel exhaust particles and particulate matter with a diameter of less than 10 µm (PM10D). To induce airway inflammation, PM10D was intranasally injected into BALB/c mice three times a day for 12 days, and LM extracts were given orally once per day. The immune cell subtypes, histopathology, and expression of inflammatory mediators were analyzed from the bronchoalveolar lavage fluid (BALF) and lungs. LM alleviated the accumulation of neutrophils and the number of inflammatory cells in the lungs and the BALF of the PM10D-exposed mice. LM also reduced the release of inflammatory mediators (MIP-2, IL-17, IL-1α, CXCL1, TNF-α, MUC5AC, and TRP receptor channels) in the BALF and lungs. Lung histopathology was used to examine airway inflammation and the accumulation of collagen fibers and inflammatory cells after PM10D exposure and showed that LM administration improved this inflammation. Furthermore, LM extract inhibited the MAPK and NF-κB signaling pathway in the lungs and improved expectoration activity through an increase in phenol red release from the trachea. LM alleviated PM10D-exposed neutrophilic airway inflammation by suppressing MAPK/NF-κB activation. This study indicates that LM extract may be an effective therapeutic agent against inflammatory respiratory diseases.

TRIM11 Prevents Ferroptosis in model of asthma by UBE2N-TAX1BP1 signaling

Asthma is a complex chronic respiratory inflammatory disease affected by both genetic and environmental factors. Therefore, our study explored the influence of TRIM11 on asthma and its underlying mechanisms. Our research involved patients diagnosed with asthma and healthy volunteers recruited from our hospital. We observed a reduction in serum TRIM11 expression in asthma patients, which positively correlated with the levels of anti-IgE or IgE. Additionally, both TRIM11 mRNA and protein expression in lung tissue were diminished. The introduction of the TRIM11 gene resulted in a reduction in inflammation in an in vitro asthma model and prevented the development of asthma in a mouse model. Moreover, the TRIM11 gene exhibited a suppressive effect on Ferroptosis and mitigated ROS-induced mitochondrial damage in the asthma model. TRIM11 was found to stimulate UBE2N-TAX1BP1 signaling in the asthma model, with UBE2N being identified as the specific target for TRIM11’s effects on Ferroptosis. Furthermore, TRIM11 protein interacted with UBE2N protein and facilitated the dissociation of UBE2N-UBE2N in the asthma model. In conclusion, TRIM11 plays a vital role in preventing Ferroptosis in the asthma model through UBE2N-TAX1BP1 signaling. This indicates that targeting the TRIM11 mechanism could serve as a promising strategy for anti-Ferroptosis immunotherapy in asthma treatment.

On the pathogenesis of COVID-19: the role of transforming growth factor beta

Proteins of the transforming growth factor beta (TGF-β) family regulate numerous cellular processes that are essential in the pathogenesis of acute respiratory distress syndrome (ARDS), contributing to increased alveolar epithelial permeability, activation of fibroblasts, and extracellular matrix remodeling. TGF-β is involved in the pathogenesis of inflammatory respiratory diseases during the development of COVID-19. SARS-CoV-2 leads to complex immune responses that include the release of inflammatory cytokines, increased activity of mast cells, and the release of mast cell secretome, in particular profibrotic enzymes and cytokines, including TGF-β.Tryptaseand chymase-positive mast cells play a major role in pulmonary fibrosis and embolism in COVID-19. Mast cell chymase is angiotensin-converting enzyme 2-independent due to extracellular formation of angiotensin II in the interstitium; it also activates TGF-β and other molecules, thereby playing a role in tissue remodeling. Mast cell β-tryptase increases the secretion of TGF-β1 by airway smooth muscle tissue and the expression of α-smooth muscle actin (α-SMA). TGF-β also induces the generation of mitochondrial reactive oxygen species (ROS), which enhances the production of ROS in lung fibroblasts. TGF-β is crucial for induing the synthesis of extracellular matrix components by fibroblasts.The review is devoted to the structure of TGF-β, the sources of its secretion and functions, the mechanism of its involvement in the pathogenesis of COVID-19, and the possibility of its use as a prognostic marker of COVID-19 severity.

A Critical Review on Bharangi (Clerodendrum serratum. Linn) with special reference to Brihat Trayi (Charak Samhita, Sushruta Samhita and Ashtanga Samhita)

Bharangi (Clerodendrum serratum) holds a significant place in Ayurvedic medicine, with extensive references in classical texts such as Charaka Samhita, Sushruta Samhita, and Ashtanga Samhita, collectively known as the Brihat Trayi. This critical review delves into the traditional uses and therapeutic applications of Bharangi as documented in these ancient texts, alongside an examination of contemporary scientific research. Emphasizing its role in managing respiratory ailments, inflammatory diseases, and other health conditions, the review aims to explore the use of Bharangi in Samhita kala and enlighten the different formulations where Bharangi is used as one of the Ingredients. This paper seeks to provide a comprehensive understanding of Bharangi’s medicinal potential and enlist the formulations that include Bharangi in it.

Advances in modern Balneology: new evidence-based indications from recent studies.

Balneotherapy (BT) is a therapeutic approach that utilizes various forms of water-based treatments to promote health and well-being. BT possesses a rich historical heritage and has garnered recognition from esteemed institutions such as the World Health Organization (WHO). Recent scientific research enables the identification of relevant diseases (obesity, metabolic diseases, sleep disorders, mental health conditions, Long-COVID-19, and cancer rehabilitation) that could potentially benefit from balneo-therapeutic treatments, thereby presenting new avenues of opportunity for SPA ("Salus per Aquam") medicine. These conditions exemplify the potential benefits of BT for ailments beyond the traditional scope of treatment associated with BT (most commonly osteoarthritis, fibromyalgia, rheumatic back pain, and chronic inflammatory respiratory or skin disorders). Overall, the current scientific evidence suggests that BT holds significant potential for enhancing both individual wellbeing and public health. However, further high-quality clinical trials are essential to corroborate these preliminary findings and to provide critical insights into the therapeutic benefits of BT, paving the way for its broader integration into healthcare practices and public health initiatives.

The Role of Transforming Growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD).

Asthma and chronic obstructive pulmonary disease (COPD) represent chronic inflammatory respiratory disorders that, despite having distinct pathophysiological underpinnings, both feature airflow obstruction and respiratory symptoms. A critical component in the pathogenesis of each condition is the transforming growth factor-β (TGF-β), a multifunctional cytokine that exerts varying influences across these diseases. In asthma, TGF-β is significantly involved in airway remodeling, a key aspect marked by subepithelial fibrosis, hypertrophy of the smooth muscle, enhanced mucus production, and suppression of emphysema development. The cytokine facilitates collagen deposition and the proliferation of fibroblasts, which are crucial in the structural modifications within the airways. In contrast, the role of TGF-β in COPD is more ambiguous. It initially acts as a protective agent, fostering tissue repair and curbing inflammation. However, prolonged exposure to environmental factors such as cigarette smoke causes TGF-β signaling malfunction. Such dysregulation leads to abnormal tissue remodeling, marked by excessive collagen deposition, enlargement of airspaces, and, thus, accelerated development of emphysema. Additionally, TGF-β facilitates the epithelial-to-mesenchymal transition (EMT), a process contributing to the phenotypic alterations observed in COPD. A thorough comprehension of the multifaceted role of TGF-β in asthma and COPD is imperative for elaborating precise therapeutic interventions. We review several promising approaches that alter TGF-β signaling. Nevertheless, additional studies are essential to delineate further the specific mechanisms of TGF-β dysregulation and its potential therapeutic impacts in these chronic respiratory diseases.

Stem cells, Notch-1 signaling, and oxidative stress: a hellish trio in cancer development and progression within the airways. Is there a role for natural compounds?

Notch-1 signaling plays a crucial role in stem cell maintenance and in repair mechanisms in various mucosal surfaces, including airway mucosa. Persistent injury can induce an aberrant activation of Notch-1 signaling in stem cells leading to an increased risk of cancer initiation and progression. Chronic inflammatory respiratory disorders, including chronic obstructive pulmonary disease (COPD) is associated with both overactivation of Notch-1 signaling and increased lung cancer risk. Increased oxidative stress, also due to cigarette smoke, can further contribute to promote cancer initiation and progression by amplifying inflammatory responses, by activating the Notch-1 signaling, and by blocking regulatory mechanisms that inhibit the growth capacity of stem cells. This review offers a comprehensive overview of the effects of aberrant Notch-1 signaling activation in stem cells and of increased oxidative stress in lung cancer. The putative role of natural compounds with antioxidant properties is also described.

Endotype and Phenotype Related Postoperative Effects of Bacterial Lysate in Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) endotypes have demonstrated clinical value in guiding treatment decisions. Bacterial lysates are immunomodulators that have shown beneficial effects in various respiratory inflammatory diseases. This study aimed to evaluate the effect of postoperative bacterial lysate therapy on different CRS endotypes. Patients diagnosed with CRS who underwent endoscopic sinus surgery were recruited. Bacterial lysates were administered postoperatively for 10 days per month for 3 months to the experimental group comprising patients with a history of frequent upper respiratory infections without adverse reactions. The remaining participants were allocated to the control group. The results of the postoperative 3-, 6-, and 12-month assessments, including the modified Lund-Kennedy (mLK) endoscopic and Sinonasal Outcome Test (SNOT) 22 scores, for the groups were compared. The tissue samples obtained from the participants were evaluated to detect the presence of relevant inflammatory mediators. Among the 92 participants, 47 started bacterial lysate therapy 2 weeks after the surgery. The tissue cytokine profiles and clinical parameters, such as the disease severity and blood eosinophil percentage, of the bacterial lysate and control groups were comparable before treatment. The mLK endoscopic and SNOT-22 scores did not differ after 3, 6, and 12 months of follow-up. The subgroup analysis revealed that the bacterial lysate group had significantly lower mLK endoscopic scores than the control group for CRS without nasal polyps, while there was a tendency toward significance for the interleukin (IL)-5 negative group after 6 months. Postoperative bacterial lysate therapy has some beneficial effects on the endoscopic findings of patients with CRS without nasal polyps or those who are negative for IL-5.

Association between house dust endotoxin and kidney injury: findings from the national health and nutrition examination survey (NHANES) 2005-2006.

House dust endotoxin is thought to be associated with systemic inflammatory responses and respiratory diseases. Previous studies have indicated that lung injury and systemic inflammation could lead to kidney damage. However, the potential link between house dust endotoxin and the increased risk of kidney injury remains unexplored. This cross-sectional study and retrospective study aim to investigate the relationship between house dust endotoxin levels and renal markers, specifically the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), utilizing data from the NHANES 2005-2006 survey cycle. Proteinuria was assessed using the UACR, with values categorized into negative (UACR ≤ 30mg/g) and positive (UACR > 30mg/g) groups. Significant differences in house dust endotoxin levels were observed between these groups (p value = 0.003). Weighted logistic regression analysis indicated that higher levels of house dust endotoxin were associated with an increased rate of positive UACR (OR [95% CI]: 1.57 [1.20, 2.05]; p value = 0.003). This association remained significant after adjusting for covariates such as age, gender, race, poverty income ratio (PIR), Type 2 Diabetes Mellitus (T2DM), and hypertension (OR [95% CI]: 1.46 [1.08, 1.97]; p-Value = 0.021). However, no significant correlation was found between house dust endotoxin levels and eGFR (Estimate [95% CI]: 1.19 [-1.28, 3.66]; p value = 0.32). Our findings suggest a significant association between house dust endotoxin levels and proteinuria, based on data from the NHANES 2005-2006 survey cycle. This association indicates that elevated levels of house dust endotoxin may be linked to kidney damage. Further research is necessary to elucidate the specific relationship between exposure to house dust endotoxin and the risk of developing kidney disease.

Quercetin alleviates inflammation induced by porcine reproductive and respiratory syndrome virus in MARC-145 cells through the regulation of arachidonic acid and glutamine metabolism.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe inflammatory response, respiratory disease and sow reproductive failure. Quercetin is among the widely occurring polypheno found abundantly in nature. Quercetin has anti-inflammatory, anti-oxidative and anti-viral properties. This study aimed to explore the effect and mechanism of quercetin on PRRSV-induced inflammation in MARC-145 cells. Observing the cytopathic effect and measurements of inflammatory markers in MARC-145 cells collectively demonstrate that quercetin elicits a curative effect on PRRSV-induced inflammation. Liquid chromatography-mass spectrometry was further used for a non-targeted metabolic analysis of the role of quercetin in the metabolic regulation of PRRSV inflammation in MARC-145 cells. It was shown that quercetin attenuated PRRSV-induced cytopathy in MARC-145 cells. Quercetin treatment inhibited PRRSV replication in MARC-145 cells in a dose-dependent manner. We also found that quercetin inhibited PRRSV-induced mRNA expression and secretion levels of tumour necrosis factor-α, interleukin 1β and interleukin 6. Metabolomics analysis revealed that quercetin ameliorated PRRSV-induced inflammation. Pathway analysis results revealed that PRRSV-induced pathways including arachidonic acid metabolism, linoleic acid, glycerophospholipid and alanine, aspartate and glutamate metabolism were suppressed by quercetin. Moreover, we confirmed that quercetin inhibited the activation of NF-κB/p65 pathway, probably by attenuating PLA2, ALOX and COX mRNA expression. These results provide a crucial insight into the molecular mechanism of quercetin in alleviating PRRSV-induced inflammation.

Pathophysiology and genomics of bronchiectasis.

Bronchiectasis is a complex and heterogeneous inflammatory chronic respiratory disease with an unknown cause in around 30-40% of patients. The presence of airway infection together with chronic inflammation, airway mucociliary dysfunction and lung damage are key components of the vicious vortex model that better describes its pathophysiology. Although bronchiectasis research has significantly increased over the past years and different endotypes have been identified, there are still major gaps in the understanding of the pathophysiology. Genomic approaches may help to identify new endotypes, as has been shown in other chronic airway diseases, such as COPD.Different studies have started to work in this direction, and significant contributions to the understanding of the microbiome and proteome diversity have been made in bronchiectasis in recent years. However, the systematic application of omics approaches to identify new molecular insights into the pathophysiology of bronchiectasis (endotypes) is still limited compared with other respiratory diseases.Given the complexity and diversity of these technologies, this review describes the key components of the pathophysiology of bronchiectasis and how genomics can be applied to increase our knowledge, including the study of new techniques such as proteomics, metabolomics and epigenomics. Furthermore, we propose that the novel concept of trained innate immunity, which is driven by microbiome exposures leading to epigenetic modifications, can complement our current understanding of the vicious vortex. Finally, we discuss the challenges, opportunities and implications of genomics application in clinical practice for better patient stratification into new therapies.

Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.

Psoralen attenuates cigarette smoke extract-induced inflammation by modulating CD8+ T lymphocyte recruitment and chemokines via the JAK2/STAT1 signaling pathway

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Psoralen (PSO) is the main pharmacological component identified from Bu-Shen-Fang-Chuan formula which has been traditionally used in treatment of COPD, yet its efficacy in COPD inflammation were unreported. In this study, we aimed to elucidate the anti-inflammatory potential of PSO in COPD and unravel the underlying mechanisms, focusing on T lymphocyte recruitment and the modulation of chemokines, namely monokine induced by interferon-gamma (CXCL9), interferon inducible protein 10 (CXCL10), and interferon inducible T-Cell alpha chemoattractant (CXCL11). In vitro, RAW264.7 was stimulated by interferon (IFN)-γ + cigarette smoke extract (CSE) and were treated with PSO (2.5, 5, 10 μM), then the levels of chemokines and the activation of Janus kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) pathway were analyzed by real time PCR and western blot. In vivo, a murine model was established by intraperitoneal injection of CSE on day 1, 8, 15, and 22, then treated with PSO (10 mg/kg). Our experiments in vitro illustrated that PSO reduced the levels of CXCL9, CXCL10, and CXCL11, and decreased the protein phosphorylation levels of JAK2 and STAT1. Additionally, PSO effectively improved inflammatory infiltration and decreased the proportion of CD8+ T cells in CSE-exposed mice. Furthermore, PSO reduced the levels of CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid (BALF) and lung tissue, and decreased the protein phosphorylation levels of JAK2 and STAT1. In conclusion, our results revealed the therapeutic potential of PSO for COPD inflammation, possibly mediated through the regulation of CD8+ T cell recruitment and chemokines via the JAK2/STAT1 signaling pathway.

A novel 12-membered ring non-antibiotic macrolide EM982 attenuates cytokine production by inhibiting IKKβ and IκBα phosphorylation

Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors. Macrolide antibiotics such as erythromycin (EM) have immunomodulatory effects in addition to their antibacterial activity. Long-term, low-dose administration of macrolides has shown clinical benefits in treating non-infectious inflammatory respiratory diseases. However, this practice may also increase the emergence of drug-resistant bacteria. In this study, we synthesized a series of EM derivatives, and screened them for two criteria: (i) lack of antibacterial activity and (ii) ability to suppress tumor necrosis factor-α (TNF-α) production in THP-1cells stimulated with lipopolysaccharide. Among the 37 synthesized derivatives, we identified a novel 12-membered ring macrolide EM982 that lacked antibacterial activity against Staphylococcus aureus and suppressed the production of TNF-α and other cytokines. The effects of EM982 on Toll-like receptor 4 (TLR4) signaling were analyzed using a reporter assay and Western blotting. The reporter assay showed that EM982 suppressed the activation of transcription factors, NF-κB and/or activator protein 1 (AP-1), in HEK293cells expressing human TLR4. Western blotting showed that EM982 inhibited the phosphorylation of both IκB kinase (IKK) β and IκBα, which function upstream of NF-κB, whereas it did not affect the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase, which act upstream of AP-1. These results suggest that EM982 suppresses cytokine production by inhibiting phosphorylation of IKKβ and IκBα, resulting in the inactivation of NF-κB.