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Eosinophils, traditionally associated with allergic phenomena, play a pivotal role in inflammatory responses. Despite accumulating evidence suggesting their pro-inflammatory function upon activation, the underlying mechanisms governing eosinophil activation remain incompletely characterized. In this study, we investigate the local activation of pulmonary and colon eosinophils within the inflammatory microenvironment. Leveraging transcriptional sequencing, we identify TGF-β as a putative regulator of eosinophil activation, leading to the secretion of granule proteins, including peroxidase. Genetic deletion of TGF-β receptors on eosinophils resulted in the inhibition of peroxidase synthesis, affirming the significance of TGF-β signaling in eosinophil activation. Using models of HDM-induced asthma and DSS-induced colitis, we demonstrate the indispensability of TGF-β-driven eosinophil activation in both disease contexts. Notably, while TGF-β signaling did not significantly influence asthmatic inflammation, its knockout conferred protection against experimental colitis. This study delineates a distinct pattern of eosinophil activation within inflammatory responses, highlighting the pivotal role of TGF-β signaling in regulating eosinophil behavior. These findings deepen our comprehension of eosinophil-related pathophysiology and may pave the way for targeted therapeutic approaches in allergic and inflammatory diseases., (© 2024. The Author(s).)

(1) Background: Chronic inflammation has been regarded as a risk factor for the onset and progression of human cancer, but the critical molecular mechanisms underlying this pathological process have yet to be elucidated. (2) Methods: In this study, we investigated whether interleukin (IL)-17-mediated inflammation was involved in cigarette smoke-induced genomic instability. (3) Results: Higher levels of both IL-17 and the DNA damage response (DDR) were found in the lung tissues of smokers than in those of non-smokers. Similarly, elevated levels of IL-17 and the DDR were observed in mice after cigarette smoke exposure, and a positive correlation was observed between IL-17 expression and the DDR. In line with these observations, the DDR in the mouse lung was diminished in IL-17 KO when exposed to cigarette smoke. Besides this, the treatment of human bronchial epithelium cells with IL-17 led to increased levels of the DDR and chromosome breakage. (4) Conclusions: These results suggest that cigarette smoke induces genomic instability at least partially through IL-17-mediated inflammation, implying that IL-17 could play an important role in the development of lung cancer.

Introduction: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma., Methods: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b -/- mice were used for allergic models., Results: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice.-/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice., Conclusion: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma., Competing Interests: Competing interests: AMKC is a cofounder, stock holder and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. AMKC also has a use patent on CO. No other authors have any conflicts of interests., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma., (Copyright © 2018. Published by Elsevier Ltd.)

Rationale: The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis., Objectives: To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation., Methods: A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma., Measurement and Main Results: Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin., Conclusions: These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

Chronic airway inflammatory diseases are life-threatening conditions, including bronchial asthma, chronic obstructive pulmonary disease (COPD), and so on. However, as the disease etiology remains largely unclear, current treatments that target chronic airway inflammatory diseases are still not satisfactory. DNA damage response (DDR), regarded as one of the many causes of apoptosis and cell senescence, as well as a factor involved in carcinogenesis, has recently begun to attract attention as a source of chronic inflammation. Considering that COPD and allergic asthma inflammation enhance DNA damage, measures related with DNA repair should be taken so as to reduce the injuries caused by these airway diseases. Small molecule inhibitors specifically against various DNA repair proteins have been developed over the last decade to fight against chronic diseases. Poly(ADP-ribose) polymerase (PARP) inhibitor, for example, has already shown its potential in asthma animal models to block airway inflammation. In this review, we highlight the roles of DDR in chronic airway inflammatory diseases, and try to have a better understanding of these diseases. We also discuss the possibilities of targeting DDR signaling to develop potential novel treatments against these conditions.

Introduction: We performed a meta-analysis on whether heated humidification during positive airway pressure (PAP) could improve compliance and subjective daytime sleepiness in obstructive sleep apnea syndrome (OSAS) patients. Materials and methods: We searched PubMed, EMBASE, Medline, Cochrane Library, Clinical Trials, Web of Science and Scopus from inception to Oct 29, 2017. We made meta-analysis on the all available randomized controlled trials (RCTs) which assessed effects of heated humidification intervention on PAP compliance and subjective daytime sleepiness, by subgroups of automatic adjusting positive airway pressure/ continuous positive airway pressure (APAP/CPAP) usage and patients with/without upper airway symptoms prior to PAP therapy. Results: A total of nine RCTs were evaluated finally in this meta-analysis. When all the studies were pooled, heated humidification did not improve PAP usage time [weighted mean difference(WMD) = 13.28, 95% confidence interval(CI): -5.85 to 32.41, P = 0.17] or Epworth sleepiness scale (ESS) score (WMD = -0.63, 95% CI: -1.32 to 0.07, P = 0.08). In terms of PAP usage time, heated humidification failed to enhance compliance in both APAP (WMD = 22.34, 95%CI: -21.08 to 65.77, P = 0.31) or CPAP subgroup (WMD = 11.09, 95%CI: -10.21 to 32.40, P = 0.31) and it was also ineffective among patients with upper airway symptoms prior to PAP therapy (WMD = 22.74, 95% CI: -7.77 to 53.24, P = 0.14) or without (WMD = 13.22, 95%CI: -35.84 to 62.29, P = 0.60). In terms of ESS score, heated humidification did not reduce ESS scores in both APAP (WMD = -1.59, 95% CI: -3.81 to 0.64, P = 0.16) or CPAP subgroup (WMD = -0.39, 95% CI: -1.16 to 0.37, P = 0.32) and it was also helpless among patients with upper airway symptoms prior to PAP therapy (WMD = -1.17, 95% CI: -3.10 to 0.75, P = 0.23) or without (WMD = -0.30, 95%CI: -2.25 to 1.66, P = 0.76). Conclusion: Heated humidification during PAP therapy improves neither the compliance nor ESS scores in OSAS patients, no matter what types of PAP or whether the patients had upper airway symptoms prior to PAP therapy. But to the population with upper airway symptoms and the APAP users, the conclusions were limited because of small sample size and possible selection bias. More attentions should be paid to these potentially possible benefited subgroups. [ABSTRACT FROM AUTHOR]

Eosinophil‐deficient MBP‐1 and EPX double‐knockout mice show how eosinophils are necessary for increased IL‐4/IL‐13 expression linked with acute and chronic pulmonary inflammation. Eosinophils and the release of cationic granule proteins have long been implicated in the development of the type 2–induced pathologies linked with respiratory inflammation. Paradoxically, the ablation of the two genes encoding the most abundant of these granule proteins, major basic protein‐1 (MBP‐1) and eosinophil peroxidase (EPX), results in a near collapse of eosinophilopoiesis. The specificity of this lineage ablation and the magnitude of the induced eosinopenia provide a unique opportunity to clarify the importance of eosinophils in acute and chronic inflammatory settings, as well as to identify potential mechanism(s) of action linked with pulmonary eosinophils in those settings. Specifically, we examined these issues by assessing the induced immune responses and pathologies occurring in MBP‐1−/−/EPX−/− mice after 1) ovalbumin sensitization/provocation in an acute allergen‐challenge protocol, and 2) crossing MBP‐1−/−/EPX−/− mice with a double‐transgenic model of chronic type 2 inflammation (i.e., I5/hE2). Acute allergen challenge and constitutive cytokine/chemokine expression each induced the accumulation of pulmonary eosinophils in wild‐type controls that was abolished in the absence of MBP‐1 and EPX (i.e., MBP‐1−/−/EPX−/− mice). The expression of MBP‐1 and EPX was also required for induced lung expression of IL‐4/IL‐13 in each setting and, in turn, the induced pulmonary remodeling events and lung dysfunction. In summary, MBP‐1−/−/EPX−/− mice provide yet another definitive example of the immunoregulatory role of pulmonary eosinophils. These results highlight the utility of this unique strain of eosinophil‐deficient mice as part of in vivo model studies investigating the roles of eosinophils in health and disease settings. [ABSTRACT FROM AUTHOR]

Shp2 played an important role in cigarette-smoke-mediated inflammation, surfactant homeostasis and asthmatic airway remodeling. However, whether shp2 plays a key role in epithelium-associated allergic reaction is still unknown. In this study, LPS and OVA were observed to induce the production of IL-25 in bronchial epithelial cells in vitro via the activation of MAPK p38 and JNK. Furthermore, blockage of Shp2 by its specific inhibitor PHPS1 or by siRNA-mediated depletion was found to reduce the production of IL-25 in epithelial cells as well as the up-regulated LPS-triggered activation of JNK but not p38. To confirm the role of intra-bronchial epithelial Shp2 in OVA-induced allergic reaction, we generated CC10-rtTA/(tetO)7-Cre/Shp2f/f mice, where Shp2 was conditionally knocked out in bronchial epithelial cells. Surprisingly, specific deletion of Shp2 in bronchial epithelial cells showed a mild but insignificant effect on the expressions of epithelium-derived cytokines as well as TH2 and TH17 polarization following allergen-induced murine airway inflammation. Collectively, our data suggested that deletion of Shp2 impaired IL-25 production in bronchial epithelial cells in vitro, but might yet have minor influence on OVA-induced allergic reaction in vivo. [ABSTRACT FROM AUTHOR]

Background and objective Some types of T lymphocytes, especially cytotoxic T-cells ( Tc1) and T-helper ( Th17) cells, play a pivotal role in cigarette smoke-induced lung diseases. However, whether Tc17 cells are involved remains largely unknown. We investigated Tc17 involvement using a cigarette smoke-exposure model. Methods Groups of mice were exposed to cigarette smoke or filtered air. At weeks 2, 8, 12 and 24, mice were sacrificed to observe histological changes by HE stain and/or immunohistochemical staining. The frequency of T cell subsets in the lung and spleen were detected by flow cytometry. In addition, the expression levels of T cell-related factors were measured by real-time polymerase chain reaction or enzyme-linked immunosorbent assay. Results Cigarette smoke caused substantial inflammatory cell infiltration and led to emphysema. Cigarette smoke exposure promoted the expression of interferon-gamma ( IFN)-γ and interleukin ( IL)-17 A at the messenger ribonucleic acid and protein levels. In addition to Tc1 and Th17 cells, pulmonary and splenic Tc17 cells increased, which was accompanied by the upregulation of cytokines IL-6, transforming growth factor beta ( TGF)-β) and transcriptional factors Stat3 and RAR-related orphan receptor gamma. Compared with untreated mice, γ H2 AX-positive cells were more frequently observed in mice exposed to cigarette smoke. Conclusions Long-term cigarette smoke exposure induced Tc17 cell expansion both locally and distally, which was associated with emphysema and deoxyribonucleic acid damage. As an important source of IL-17 A, this T cell subset may be a potential target for chronic obstructive pulmonary disease therapy. [ABSTRACT FROM AUTHOR]

A strategy to deplete eosinophils from the lungs of ovalbumin (OVA)-sensitized/challenged mice was developed using antibody-mediated depletion. Concurrent administration [viz. the peritoneal cavity (systemic) and as an aerosol to the lung (local)] of a rat anti-mouse CCR3 monoclonal antibody resulted in the abolition of eosinophils from the lung such that the airway lumen was essentially devoid of eosinophils. Moreover, perivascular/peribronchial eosinophil numbers were reduced to levels indistinguishable from saline-challenged animals. This antibody-mediated depletion was not accompanied by effects on any other leukocyte population, including, but not limited to, T cells and mast cells/basophils. In addition, no effects were observed on other underlying allergic inflammatory responses in OVA-treated mice, including OVA-specific immunoglobulin production as well as T cell-dependent elaboration of Th2 cytokines. The ablation of virtually all pulmonary eosinophils in OVA-treated mice (i.e., without concurrent effects on T cell activities) resulted in a significant decrease in mucus accumulation and abolished allergen-induced airway hyperresponsiveness. These data demonstrate a direct causative relationship between allergen-mediated pulmonary pathologies and eosinophils. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) has been implicated as a risk factor for human airway disorders. However, the biological mechanisms underlying the correlation between PM exposure and adverse airway effects have not yet been fully clarified. The objective of this study was to explore the possible role of early growth response gene 1 (Egr-1) in PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction in vitro and in vivo. Particulate matter exposure induced a rapid Egr-1 expression in human bronchial epithelial (HBE) cells and in mouse lungs. Genetic blockage of Egr-1 markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells, and these effects were mechanistically mediated by the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways, respectively. Egr-1-knockout mice displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Moreover, polycyclic aromatic hydrocarbons (PAHs) contained in the PM also induced Egr-1 expression, and also played a role in the inflammatory responses and mucus production. Taken together, our data reveal novel Egr-1 signaling that mediates the NF-κB and AP-1 pathways to orchestrate PM-induced pulmonary inflammation and mucus hyperproduction, suggesting that Egr-1 inhibition could be an effective therapeutic approach for airway disorders or disease exacerbations induced by airborne particulate pollution. [ABSTRACT FROM AUTHOR]

Airborne particulate matter (PM) has been reported to be associated with a wide range of respiratory disorders. However, the mechanisms underlying PM-induced airway inflammation remain largely unknown. Generally, ATF3 negatively regulates pro-inflammatory cytokines production in response to TLR4 signaling. Here we first showed ATF3 has promoting effects in PM-induced airway inflammation in vitro an in vivo . We demonstrated PM significantly upregulated ATF3 expression in HBE cells and in mouse lung tissues. ATF3 siRNA markedly inhibited, while ATF3-recombinant over-expression plasmid significantly increased PM-induced IL-6 expression in cultured HBE cells, and PM-induced IL-6, CXCL2 expression as well as neutrophil infiltration, mucus over-production in the lung of ATF3 −/− mice were all notably reduced relative to the wild-type littermates. Furthermore, we showed ATF3 mediated PM-induced inflammatory cytokines expression partly through NF-κB and AP-1 pathways. Our data further elucidates the mechanisms underlying PM-induced airway inflammation, and indicates ATF3 may function as different role in response to different stimuli. [ABSTRACT FROM AUTHOR]

Aims Therapeutic hypothermia has shown beneficial effects in sepsis. This study focused on its mechanism. Main methods Sixteen male Sprague-Dawley rats underwent cecal ligation and perforation and subsequently were treated with either hypothermia (HT; body temperature cooled and maintained at 34 °C by ice pad for 10 h; n  = 8) or normothermia (NT; n = 8). Three additional rats underwent sham surgery. The body temperatures of the sham-operated and NT groups were maintained at 38 °C with a thermal pad. After the hypothermia treatment, the HT rats were rewarmed for 2 h. The groups were compared for circulating cytokines (IL-6, IL-10), lactate, high mobility group box-1 protein (HMGB1), and lung and intestinal lesions. Animals were observed for 24 h. Key findings Compared with the sham-operated group, the 2 sepsis group rats had significantly higher circulating IL-6, HMGB1, and lactate levels, and tissue injury. In the HT rats, the levels of IL-6, HMGB1, and lactate, the lung wet-to-dry ratio, and lung and intestinal damage were significantly lower than that of the NT group. Circulating IL-10 levels increased significantly after 12 h in the sepsis groups compared with sham animals, while that of the NT and HT groups were comparable. The survival rates of the NT and HT rats were also comparable. Significance Therapeutic hypothermia in a rat model of sepsis was associated with lower levels of circulating IL-6 and HMGB1, and less capillary leakage and tissue edema. These results suggest that mild hypothermia has potential as a therapy in sepsis. [ABSTRACT FROM AUTHOR]

Background: Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular bases for their involvement are unknown.Methods and Results: We generated a new strain (ApX4) of apolipoprotein E-deficient mice expressing a membrane-tethered human tissue factor pathway inhibitor fusion protein on smooth muscle actin-positive cells, including vascular smooth muscle cells (SMCs). ApX4 mice developed little atherosclerosis on either a normal chow or high-fat diet. Lipid levels were similar to those in parental ApoE(-/-) mice, and there was no detectable difference in systemic (circulating) tissue factor pathway inhibitor levels or activity. The small lipid-rich lesions that developed had markedly reduced leukocyte infiltrates, and in contrast to ApoE(-/-) mice, SMCs did not express macrophage migratory inhibitory factor (MIF), including at sites distant from atheromatous lesions. Low levels of circulating MIF in ApX4 mice normalized to levels seen in ApoE(-/-) mice after injection of an inhibitory anti-human tissue factor pathway inhibitor antibody, which also led to MIF expression by tissue factor-positive medial SMCs. MIF production by SMCs in ApoE(-/-) mice in vitro and in vivo was shown to be dependent on tissue factor and protease-activated receptor signaling, which were inhibited in ApX4 mice.Conclusions: Our data indicate that tissue factor plays a hitherto unreported role in the generation of MIF by SMCs in atherosclerosis-prone ApoE(-/-) mice, inhibition of which significantly prevents the development of atherosclerosis, through inhibition of leukocyte recruitment. These data significantly enhance our understanding of the pathophysiology of this important pathology and suggest new potential translational strategies to prevent atheroma formation. [ABSTRACT FROM AUTHOR]

• Airway neutrophils are accumulated in asthma prior to eosinophils. • Macrophage-derived chemokines cause neutrophilia in the lungs. • Neutrophils mediate asthmatic airway inflammation exacerbation by releasing NE. • The specific inhibition of NE alleviates asthmatic airway inflammation. Neutrophils can regulate adaptive immune responses and contribute to chronic inflammation including asthma. However, the roles and mechanisms of neutrophils in initiating eosinophilic airway inflammation remain incompletely understood. Neutrophil elastase (NE) is a component of azurophilic granules and a serine protease with potent functions during inflammation. Here, we showed that neutrophils were early recruited at the onset of asthmatic inflammation by related chemokines. Furthermore, neutrophils could capture allergens and release NE to promote neutrophil aggregation at first. Then they prompt eosinophil infiltration and amplify type 2 immune responses in later phases. Also, this process can be rescued by administration of the NE inhibitor (GW311616). Our data collectively indicate that neutrophils could contribute to asthmatic inflammation by releasing NE. [ABSTRACT FROM AUTHOR]