PANoptosis opens new treatment options for allergic bronchopulmonary aspergillosis.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a rare airway disorder primarily affecting patients with asthma and cystic fibrosis. Persistent airway inflammation brought on by Aspergillus fumigatus exacerbates the underlying condition and can cause significant respiratory damage. Treatments center on reducing inflammation with the use of corticosteroids and antifungals. PANoptosis is a new concept in the field of cell death and inflammation that posits the existence of cross talk and a master control system for the 3 programmed cell death (PCD) pathways, namely, apoptosis, pyroptosis, and necroptosis. This concept has revolutionized the understanding of PCD and opened new avenues for its exploration. Studies show that Aspergillus is one of the pathogens that is capable of activating PANoptosis via the Z-DNA binding protein 1 (ZBP1) pathway and plays an active role in the inflammation caused by this organism. Objective: This article explores the nature of inflammation in ABPA and ways in which PCD could lead to novel treatment options. Method: PubMed was used to review the literature surrounding Aspergillus infection-related inflammation and PANoptosis. Results: There is evidence that apoptosis and pyroptosis protect against Aspergillus-induced inflammation, whereas necroptosis promotes inflammation. Conclusion: Experimental medications, in particular, necroptosis inhibitors such as necrosulfonamide and necrostatin-1, should be studied for use in the treatment of ABPA.

EP2 inhibition restores myeloid metabolism and reverses cognitive decline.

Nonsteroidal anti-inflammatory drugs alleviate pain and inflammation by inhibiting the cyclooxygenase pathway. This pathway has various downstream effects, some of which are beneficial. Prostaglandin E2 is a key downstream product in the cyclooxygenase pathway that modulates inflammation. A correlation between aging and increased expression of the prostaglandin E2 receptor, EP2, has been associated with inflammatory processes, cognitive aging, angiogenesis, and tumorigenesis. Therefore, inhibition of EP2 could lead to therapeutic effects and be more selective than inhibiting cyclooxygenase-2. Studies suggest that inhibition of EP2 restores age-associated spatial memory deficits and synaptic proteins and impairs tumorigenesis. The data indicate that EP2 signaling is important in myeloid cell metabolism and support its candidacy as a therapeutic target.

Pyroptosis Inhibition in Disease Treatment: Opportunities and Challenges.

Programmed cell death (PCD) is at the center of immune responses, with different types of PCD occurring based on bodily conditions at a given moment. The main three types of PCD include pyroptosis, necroptosis, and apoptosis. Both pyroptosis and necroptosis induce an inflammatory response while apoptosis avoids eliciting an inflammatory reaction. Recently, pyroptosis has come to the forefront of immunology research due to tremendous potential that has been revealed surrounding the regulators of pyroptosis. In addition to previously known regulators of pyroptosis (ZBP1 and NLRP3 genes), a family of proteins called Gasdermin has been discovered. Specifically, Gasdermin D (GSDMD), when cleaved, participates in the onset of pyroptosis of inflammatory diseases. The N-terminal cleaved portion of the molecule causes cellular membrane openings releasing interleukin-18 and IL-1ß, inducing pyroptosis. It is hypothesized that the inhibition of GSDMD using drugs such as Dimethyl Fumarate (DMF) and Disulfiram may halt the progression of certain inflammatory diseases including Multiple Sclerosis (MS), autoimmune encephalitis etc. While there is not yet a concrete treatment for pyroptic cell death in inflammatory disease using GSDMD inhibition, there is ample evidence to suggest that there may be success in future studies and therapeutic applications of GSDMD.

Nuclear Export Inhibitors Selinexor (KPT-330) and Eltanexor (KPT-8602) Provide a Novel Therapy to Reduce Tumor Growth by Induction of PANoptosis.

Programmed cell death (PCD) is a process that occurs naturally in cells in response to different endogenous or exogenous factors and facilitated by specific proteins. The three common pathways are pyroptosis, necroptosis, and apoptosis. Each pathway has its own unique proteins, mechanisms, and byproducts. Dysregulated PCD can lead to abnormal growth of cells causing tumor growth, a hallmark feature of many cancer pathologies. Recently, the PCD pathways have been considered to be activated simultaneously in a combined nature defined as PANoptosis (pyroptosis, apoptosis, and necroptosis). An integral protein, Z-DNA binding protein 1 (ZBP1) aids in the initiation of the NOD-like receptor protein 3 (NLRP3) inflammasome, a known facilitator of pyroptosis. It also is known to bind to a regulator of necroptosis, receptor-interacting protein kinase 3 (RIPK3). A unique binding partner to ZBP1, adenosine deaminase acting on RNA 1 (ADAR1), is involved in RNA editing, stress mechanisms, and disease. In murine bone marrow-derived macrophages (BMDMs) treatment with nuclear export inhibitors (NEIs) has allowed for sequestering of ADAR1 to the nucleus, and increased incidence of cell death. Additionally, the use of interferons (IFNs) to induce ZBP1 has increased the incidence of cell death. Emerging therapies are looking at the efficacy of using a combination of NEI and IFN treatment to rapidly reduce tumor size and growth by inducing PANoptosis. KPT-330 and KPT-8602 are two different NEIs, both of which have shown efficacy in the reduction of tumor size and inhibition of Exportin 1 (XPO1), a transport protein. However, this article posits KPT-8602 as the better of the two. KPT-8602 is more tolerable for the patient and should be pushed to human trials.

The Cd/Zn Axis: Emerging Concepts in Cellular Fate and Cytotoxicity.

Cadmium (Cd) is a toxic and carcinogenic substance that is present in the natural environment. The underlying biomolecular mechanisms of Cd toxicity are not completely understood, and it continues to be a significant research target due to its impact on public health. The primary routes of exposure are through ingestion of contaminated food and water and inhalation. Cd's long biological half-life of 10-30 years allows it to accumulate in the body, leading to organ dysfunction notably in the kidney, liver, bone, and lungs. Cd has similar biochemical characteristics to Zinc (Zn). It shares the import transporters, ZIP8 and ZIP14, to enter the cells. This competitive behavior can be observed in multiple instances throughout the progression of Cd toxicity. Future studies on the biochemical interactions of Cd and Zn will elucidate the potential protective effects of Zn supplementation in reducing the effects of Cd toxicity. In addition, research can be focused on discovering key proteins and effective pathways for Cd elimination that confer fewer adverse effects than current antioxidant therapies.

Can PPAR γ Keep Cadmium in Check?

Cd, a naturally occurring endocrine toxin found in tobacco leaves, originates in the environment and enters the body through inhalation, targeting the lungs and kidneys. A study published by Larsen-Carey et al. revealed that cadmium mediates the persistence of classically activated lung macrophages to exacerbate lung injury. The research discovered a novel role for PPAR γ as an effective regulator for the alternative activation of macrophages in response to Cd and Cd-induced lung injury.

Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps.

Objective: Our previous studies showed an age-related increased prevalence of nasal polyps (NP) and reduced production of S100A8/9 in elderly patients with chronic rhinosinusitis with NP (CRSwNP). In this study, we investigated an unbiased age-related gene expression profile in CRSwNP subjects and healthy controls, and further identified the differences in their tissue remodeling. Methods: Microarrays using NP and uncinate tissues from health controls (elderly, age ≥65 vs. non-elderly, age 18-49) were performed, and differentially regulated genes were analyzed. Quantitative real-time PCR (qPCR), Immunostaining, Periodic acid-Schiff (PAS), trichrome staining, Western blot, and ELISA were performed for further investigation. Results: Microarrays identified differentially expressed genes according to disease and age; 278 in NP vs. controls, 75 in non-elderly NP vs. non-elderly controls, and 32 in elderly NP vs. elderly controls. qPCR confirmed that the PLAT gene was downregulated and the SERPINB2 gene upregulated in NP vs. controls. The serous glandular cell-derived antimicrobial protein/peptide-related genes such as BPIFB3, BPIFB2, LPO, and MUC7 were remarkably reduced in NP, regardless of age. SERPINE1 gene (plasminogen activator inhibitor-1, PAI-1) expression was significantly increased in elderly NP versus elderly controls. IHC and western blot confirmed significantly decreased production of MUC7 and LPO in NP versus controls. There was a trend of age-related reduction of submucosal gland cells in normal controls. Trichrome and immunofluorescence staining demonstrated an age-related increase of collagen and fibrin deposition in NP, consistent with increased PAI-1 production. Conclusion: This study demonstrated age-related differential glandular remodeling patterns and fibrosis in NP and normal controls. PAI-1 expression was significantly increased in elderly NP versus elderly controls, suggesting PAI-1 as a potential treatment target in elderly NP.

Nitrated fatty acid, 10-nitrooleate protects against hyperoxia-induced acute lung injury in mice.

The antioxidant and anti-inflammatory effects of electrophilic nitrated fatty acid (NFA); 10-nitrooleate, have been reported. The present study investigated whether 10-nitrooleate has a protective role against hyperoxic-induced acute lung injury (HALI). Using a C57BL/6 mice model of HALI, we investigated the protective effect of 10-nitrooleate. C57BL/6 mice were administered with NFA intratracheally, exposed to hyperoxia for 48 h to induce HALI, and kept at room air for 24 h. Bronchoalveolar lavage (BAL) fluid and lung samples were collected after 24 h of post hyperoxia to analyze markers associated with HALI. Intratracheal (IT) and intraperitoneal (IP) administration of NFA notably attenuated hyperoxia-induced infiltration of inflammatory cells, alveolar-capillary leakage, upregulation of proinflammatory cytokine levels (IL-6 and TNFα) into the BAL fluid, and resolution of inflammation in the lung. Western blot analyses showed that 10-nitrooleate reduced the expression of the inflammatory transcription factor NFκB p65 subunit and increased antioxidant proteins HO-1 and NQO1 expression in the lung tissues compared to vehicle-treated animals. Moreover, 10-nitrooleate reversed the hyperoxia-induced expression of mitophagy-associated markers (PINK1 and p62/SQSTM1), thereby protecting the HALI/ acute respiratory distress syndrome (ARDS). IT and IP delivery of 10-nitrooleate reduces hyperoxia-induced ALI/ARDS by regulating the antioxidant pathways and restoring the mitochondrial homeostasis by regulating mitophagy. It is suggested that NFAs can be further evaluated as supplementary therapy for critically ill patients like COVID-19/ARDS.

BMI1 Silencing Induces Mitochondrial Dysfunction in Lung Epithelial Cells Exposed to Hyperoxia.

Acute Lung Injury (ALI), characterized by bilateral pulmonary infiltrates that restrict gas exchange, leads to respiratory failure. It is caused by an innate immune response with white blood cell infiltration of the lungs, release of cytokines, an increase in reactive oxygen species (ROS), oxidative stress, and changes in mitochondrial function. Mitochondrial alterations, changes in respiration, ATP production and the unbalancing fusion and fission processes are key events in ALI pathogenesis and increase mitophagy. Research indicates that BMI1 (B cell-specific Moloney murine leukemia virus integration site 1), a protein of the Polycomb repressive complex 1, is a cell cycle and survival regulator that plays a role in mitochondrial function. BMI1-silenced cultured lung epithelial cells were exposed to hyperoxia to determine the role of BMI1 in mitochondrial metabolism. Its expression significantly decreases in human lung epithelial cells (H441) following hyperoxic insult, as determined by western blot, Qrt-PCR, and functional analysis. This decrease correlates with an increase in mitophagy proteins, PINK1, Parkin, and DJ1; an increase in the expression of tumor suppressor PTEN; changes in the expression of mitochondrial biomarkers; and decreases in the oxygen consumption rate (OCR) and tricarboxylic acid enzyme activity. Our bioinformatics analysis suggested that the BMI1 multifunctionality is determined by its high level of intrinsic disorder that defines the ability of this protein to bind to numerous cellular partners. These results demonstrate a close relationship between BMI1 expression and mitochondrial health in hyperoxia-induced acute lung injury (HALI) and indicate that BMI1 is a potential therapeutic target to treat ALI and Acute Respiratory Distress Syndrome.

Matrix Metalloproteinase 7 Expression and Apical Epithelial Defects in Atp8b1 Mutant Mouse Model of Pulmonary Fibrosis.

Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF.

Lung fibrosis is induced in ADAR2 overexpressing mice via HuR-induced CTGF signaling.

Adenosine deaminase acting on RNA 2 (ADAR2), an RNA editing enzyme is involved in a site-selective modification of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Its role in the lungs is unknown. The phenotypic characterization of Adarb1 mice that lacked ADAR2 auto-regulation due to the deletion of editing complementary sequence (ΔECS mice) determined the functional role of ADAR2 in the lungs. ADAR2 protein expression increased in the ΔECS mice. These mice display immune cell infiltration and alveolar disorganization. The lung wet by dry ratio indicates there is no lung edema in ΔECS mice. Bronchoalveolar lavage (BAL) analysis of ΔECS mice reveals a significant increase in neutrophils. Interestingly, ΔECS mice spontaneously develop lung fibrosis as indicated by Sirius red staining of collagen fibers in the lung sections and a significant increase in hydroxyproline level in their lungs. ADAR2 expression increased significantly in a bleomycin mouse model, implicating a role of ADAR2 in lung fibrosis. Furthermore, there is a likely possibility that the genetically modified ΔECS mice does not model the physiological or pathophysiological process of lung fibrosis. Nevertheless, this model is useful in interrogating the role of ADAR2 in the lungs. The Ctgf mRNA and connective tissue growth factor (CTGF) protein significantly increased in ΔECS lungs and occurs in bronchial epithelial cells. There is a significant increase in Human antigen R (ELAVL1; HuR) protein levels in ΔECS lungs and suggests a role in stabilizing Ctgf mRNA. Lung mechanics such as total respiratory resistance, Newtonian resistance and tissue damping were increased, whereas inspiratory capacity was decreased in the ΔECS mice. Taken together, these data indicate that overexpression of ADAR2 causes spontaneous lung fibrosis via HuR-mediated CTGF signaling and implicate a role for ADAR2 auto-regulation in lung homeostasis. The identification of ADAR2 target genes in ΔECS mice would facilitate a mechanistic understanding of the role of ADAR2 in the lungs and provide a therapeutic strategy for lung fibrosis.

Nicotine in E-cigarette smoke: cancer culprit?

Tobacco smoke's harmful effects are well-known; the harmful effects of tobacco smoke have been well-investigated. Nicotine in tobacco smoke contributes to the pathogenesis of various conditions, such as lung cancer, coronary artery disease and asthma. A decade ago, a seemingly safer alternative to tobacco cigarettes was introduced- the E-cigarette. However, studies have found that E-cigarette smoke (ECS) not only induces DNA damage but also reduces DNA repair activity via BER and NER pathways. Further research conducted with cells damaged by Ultra-Violet (UV) light or hydrogen peroxide (H2O2) indicates that ECS can function as a comutagen; nicotine can amplify mutagenic activity by merging with other mutagens. The downstream metabolites derived from nicotine found in ECS put E-cigarette smokers at a higher risk for developing lung or bladder cancers or heart disease than their non-smoking counterparts. Overall, these findings are instrumental in our understanding of the harmful effects of ECS.

Plasma levels of TNF-α, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23 in achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD).

An elevation of serum inflammatory biomarkers in achalasia patients compared with controls recently was demonstrated. It has not been determined whether the elevation of inflammatory cytokines is unique to achalasia or occurs with other diseases involving the esophagus. The primary aim of our study was to compare the differences in plasma immunological profiles (TNF- α receptor, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23) of patients with achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD). A secondary aim of this study was to classify these same plasma cytokine profiles in the three achalasia subtypes. METHODS: Plasma from 53 patients with achalasia, 22 with EoE, and 20 with GERD (symptoms plus esophagitis or + reflux study) were analyzed. EXCLUSION CRITERIA: malignancy, autoimmune condition, immunodeficiency disorder, and treatment with steroids/immune modulating drugs. Cytokine levels were assayed via multiplex enzyme-linked immunosorbent assay (ELISA). RESULTS: Our key finding revealed significant elevations in IL- 6 (p = 0.0158) in achalasia patients compared with EoE patients. Overall, plasma inflammatory biomarker patterns were not different in the three subtypes of achalasia. CONCLUSION: There were no differences between the cytokine levels of any of the measured biomarkers between the achalasia and GERD groups suggesting that luminal stasis does increase biomarker levels for any of the cytokines examined in our study. While these results are an early first step towards clarifying some aspects of the pathogenesis of achalasia, they bring about many more questions that require further investigation and expansion. Further investigation with a larger cohort and a broader panel of biomarkers is needed.

Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging.

Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice.

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1G308V/G308V lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.

Thyroid hormone: a resurgent treatment for an emergent concern.

The story of thyroid hormone in human physiology is one of mixed emotions. Studying past literature on its use leads one to believe that it serves only a few functions in a handful of diseases. In reality, the pathophysiological role of thyroid hormone is an uncharted expanse. Over the past few decades, research on thyroid hormone has been understandably monopolized by studies of hypo- and hyperthyroidism and cancers. However, in our focused pursuit, we have neglected to observe its role in systems that are not so easily relatable. Recent evidence in lung disease suggests that the thyroid hormone is capable of preserving mitochondria in an indirect manner. This is an exciting revelation given the profound implications of mitochondrial dysfunction in several lung diseases. When paired with known links between thyroid hormone and fibrotic pathways, thyroid hormone-based therapies become more enticing for research. In this article, we inspect the sudden awareness surrounding thyroid hormone and discuss why it is of paramount importance that further studies scrutinize the potential of thyroid hormone, and/or thyromimetics, as therapies for lung diseases.

A mitochondrial delicacy: dynamin-related protein 1 and mitochondrial dynamics.

The constant physiological flux of mitochondrial fission and fusion is inextricably tied to the maintenance of cellular bioenergetics and the fluidity of mitochondrial networks. Yet, the intricacies of this dynamic duo remain unclear in diseases that encompass mitochondrial dysregulation. Particularly, the role of the GTPase fission protein dynamin-related protein 1 (Drp1) is of profound interest. Studies have identified that Drp1 participates in complex signaling pathways, suggesting that the function of mitochondria in pathophysiology may extend far beyond energetics alone. Research indicates that, in stressed conditions, Drp1 translocation to the mitochondria leads to elevated fragmentation and mitophagy; however, despite this, there is limited knowledge about the mechanistic regulation of Drp1 in disease conditions. This review highlights literature about fission, fusion, and, more importantly, discusses Drp1 in cardiac, neural, carcinogenic, renal, and pulmonary diseases. The therapeutic desirability for further research into its contribution to diseases that involve mitochondrial dysregulation is also discussed.

Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response.

BACKGROUND: Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes. OBJECTIVES: We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium. METHODS: We used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af-exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). RESULTS: Assembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af-stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1ß alleviated pathophysiological features of Af-induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af-induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade. CONCLUSION: These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.

Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases.

Asthma, chronic obstructive pulmonary disease, and cystic fibrosis are three chronic pulmonary diseases that affect an estimated 420 million individuals across the globe. A key factor contributing to each of these conditions is mucus hypersecretion. Although management of these diseases is vastly studied, researchers have only begun to scratch the surface of the mechanisms contributing to mucus hypersecretion. Epigenetic regulation of mucus hypersecretion, other than microRNA post-translational modification, is even more scarcely researched. Detailed study of epigenetic mechanisms, such as DNA methylation and histone modification, could not only help to better the understanding of these respiratory conditions but also reveal new treatments for them. Because mucus hypersecretion is such a complex event, there are innumerable genes involved in the process, which are beyond the scope of a single review. Therefore, the purpose of this review is to narrow the focus and summarize specific epigenetic research that has been conducted on a few aspects of mucus hypersecretion in asthma, chronic obstructive pulmonary disease, cystic fibrosis, and some cancers. Specifically, this review emphasizes the contribution of DNA methylation and histone modification of particular genes involved in mucus hypersecretion to identify possible targets for the development of future therapies for these conditions. Elucidating the role of epigenetics in these respiratory diseases may provide a breath of fresh air to millions of affected individuals around the world.