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Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunityandhighlyexpressed inmucosal secretions, shownto target and inhibit neutrophil elastase (NE), cathepsinGand trypsinactivitytolimit proteolytic activity. Inaddition tothe potent anti-protease activity, SLPIhas beendemonstratedto exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-kB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, suchasChronicObstructivePulmonaryDisease(COPD)andCysticFibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mousemodel phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations. [ABSTRACT FROM AUTHOR]

Neutrophil-derived proteases are critical to the pathology of many inflammatory lung diseases, both chronic and acute. These abundant enzymes play roles in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release. They may also be released, inducing tissue damage and loss of tissue function. Historically, the neutrophil serine proteases (NSPs) have been the main subject of neutrophil protease research. Despite highly promising cell-based and animal model work, clinical trials involving the inhibition of NSPs have shown mixed results in lung disease patients. As such, the cutting edge of neutrophil-derived protease research has shifted to proteases that have had little-to-no research in neutrophils to date. These include the cysteine and serine cathepsins, the metzincins and the calpains, among others. This review aims to outline the previous work carried out on NSPs, including the shortcomings of some of the inhibitor-orientated clinical trials. Our growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation will then be discussed. Additionally, the potential of targeting these more obscure neutrophil proteases will be highlighted, as they may represent new targets for inhibitor-based treatments of neutrophil-mediated lung inflammation. [ABSTRACT FROM AUTHOR]

Outer membrane vesicles (OMVs) are small, spherical structures released from the outer membranes of Gram-negative bacteria into the surrounding environment. Investigations into OMVs range from their biogenesis and cargo composition to their ability to transfer virulence factors and modulate host immune responses. This emerging understanding of OMVs has unveiled their pivotal role in the pathogenicity of infectious diseases, shedding light on their interactions with host cells, their contributions to inflammation, their potential involvement in antimicrobial resistance, and their promising use for the development of novel treatments and therapies. Numerous studies have associated the OMVs of pathogenic bacteria with the exacerbation of inflammatory diseases, underlining the significance of understanding the mechanisms associated with these vesicles to find alternatives for combating these conditions. Additionally, OMVs possess the ability to act as decoys, absorbing and neutralizing antibiotics, which significantly diminishes the efficacy of a broad spectrum of antimicrobial agents. Another subtopic of interest is OMVs produced by commensal microbiota. These vesicles are increasingly acknowledged for their mutualistic functions, significantly influencing their host's physiology and immune responses. Consequently, OMVs play a crucial role in maintaining a balanced gut microbiota by fostering symbiotic relationships that significantly contribute to the overall health and well-being of the host. This comprehensive review aims to provide an up-to-date review of OMVs derived from Gram-negative bacteria, summarizing current research findings, and elucidating the multifaceted role of these vesicles in diverse biological contexts. [ABSTRACT FROM AUTHOR]