Chinese medical journal pulmonary and critical care medicine最新文献

Recent scientific breakthroughs have blurred traditional boundaries between innate and adaptive immunity, revealing a sophisticated network of tissue-resident cells that deliver immediate, localized immune responses. These lymphocytes not only provide rapid frontline defense but also present a paradoxical role in the pathogenesis of respiratory diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and the long-term tissue consequences of viral infections including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This review traverses the intricate landscape of lung-resident lymphocytes, delving into their origins, diverse functions, and their dualistic impact on pulmonary health. We dissect their interactions with the microenvironment and the regulatory mechanisms guiding their activity, with an emphasis on their contribution to both immune protection and immunopathology. This review aims to elucidate the complex narrative of these cells, enhancing our understanding of the development of precise therapeutic strategies to combat acute and chronic pulmonary diseases. Through this exploration, the review aspires to shed light on the potential of harnessing lung-resident lymphocytes for the treatment of respiratory conditions.

Background: Glucocorticoid-induced transcript 1 (GLCCI1) has been reported to be associated with the efficiency of inhaled glucocorticoids in patients with asthma. This study aimed to investigate the role of GLCCI1 in the regulation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) by the phosphatidylinositol 3-kinase (PI3K) pathway in the pathogenesis of allergic asthma.

Methods: The expression levels of genes encoding GLCCI1, NLRP3 inflammasome components, and PI3K pathway-related indicators were detected in cells isolated from induced sputum from patients with asthma and healthy controls. Next, we induced asthma in wild-type C57BL/6 mice and Glcci1 knockout (Glcci1 ^-/-) mice by injecting them with ovalbumin (OVA) and treated the asthmatic mice with a PI3K pathway inhibitor (LY294002) or left them untreated. We also performed adoptive transfer of macrophages into the mice and assessed lung inflammation, as well as GLCCI1, PI3K pathway component, and NLRP3 inflammasome component expression levels. Finally, primary bone marrow-derived macrophages (BMDMs) from wild-type and Glcci1 ^-/- mice were treated with OVA, either in the presence or absence of LY294002 and the NLRP3 inhibitor (MCC950), to validate our findings.

Results: The mRNA level of Glcci1 in induced sputum cells from asthmatic patients was lower compared to that of healthy controls. Additionally, Glcci1 mRNA expression correlated negatively with NLRP3 inflammasome indicators and the PI3K pathway components, as well as with IL-1β expression in induced sputum macrophages. In vivo, Glcci1 ^-/- asthmatic mice showed elevated levels of airway inflammation and NLRP3 inflammasome activation compared to wild-type asthmatic mice. Surprisingly, the efficacy of LY294002 in reducing lung tissue inflammation and NLRP3 inflammasome activity in wild-type asthmatic mice was attenuated by Glcci1 knockout. LY294002 enhanced GLCCI1 levels in macrophages within the lung tissue of wild-type asthmatic mice. Moreover, LY294002 did not inhibit lung inflammation in wild-type asthmatic mice depleted of macrophages that had received adoptive transfer of Glcci1 ^-/- BMDMs. In vitro experiments further illustrated that LY294002 suppressed NLRP3 activation by upregulating GLCCI1 expression in BMDMs. The introduction of MCC950 led to a marked decrease in NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) protein levels, but did not affect the expression levels of GLCCI1 or the phospho-protein kinase B (p-AKT)/AKT ratio.

Conclusions: GLCCI1 deficiency promotes asthma inflammation through PI3K-induced NLRP3 inflammasome activation.

Background: Necroptosis is a form of programmed cell death resulting in tissue inflammation due to the release of intracellular contents. Its role and regulatory mechanism in the context of acute lung injury (ALI) are unclear. Parkin (Prkn), an E3 ubiquitin ligase, has recently been implicated in the regulation of necroptosis. In this study, we aimed to investigate the role and mechanism of Parkin in the process of ALI.

Methods: Lipopolysaccharides (LPS)-induced mouse ALI model was utilized, and the pathological changes in lung tissues were characterized. To elucidate the roles of Parkin and necroptosis in this context, mixed lineage kinase domain-like (Mlkl) knockout mice, Prkn conditional knockout mice, and the necroptosis inhibitor were employed. Additionally, alveolar type 2 (AT2) cell-specific Parkin deletion and lineage-tracing mice were introduced to explore the specific roles and mechanisms of Parkin in AT2 cells.

Results: A dose-dependent increase in Parkin expression in mouse lung tissues following LPS administration was observed, correlating with a shift from epithelial apoptosis to necroptosis. Notably, depletion of MLKL significantly mitigated the pathological changes associated with ALI, particularly the inflammatory response. Conversely, the deletion of Parkin exacerbated the injury pathology, significantly enhancing necroptosis, particularly in AT2 cells. This led to increased inflammation and post-LPS fibrosis. However, treatment with GSK872, a necroptosis inhibitor, substantially mitigated the phenotype induced by Parkin deletion. Importantly, Parkin deletion impaired the proliferation and differentiation of AT2 cells into AT1 cells.

Conclusions: These findings underscore the multifaceted role of Parkin in the progression of lung injury, inflammation, and fibrosis through the regulation of AT2 cell necroptosis. Therefore, Parkin may hold potential as a therapeutic target for managing lung injury and fibrosis.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.

The innate immune system has a primary role in defending against external threats, encompassing viruses, bacteria, and fungi, thereby playing a pivotal role in establishing robust protection. Recent investigations have shed light on its importance in the progression of tumors, with a particular emphasis on lung cancer. Among the various signaling pathways implicated in this intricate process, the cGAS-STING pathway emerges as a significant participant. Cyclic GMP-AMP synthase (cGAS) discerns free DNA and activates the stimulator of interferon genes (STING), subsequently culminating in the secretion of cytokines and exerting inhibitory effects on tumor development. Consequently, researchers are increasingly interested in creating anticancer drugs that specifically target the cGAS-STING pathway, offering promising avenues for novel therapeutic interventions. The objective of this review is to present a comprehensive overview of the ongoing research on the cGAS-STING signaling pathway within the realm of lung cancer. The primary emphasis is on understanding its involvement in lung cancer development and assessing its viability as a target for innovative therapeutic options.

Lung cancer is a leading cause of cancer-related mortality. The tumor microenvironment is a complex and heterogeneous cellular environment surrounding tumor cells, including cancer-associated fibroblasts (CAFs), blood vessels, immune cells, the extracellular matrix, and various cytokines secreted by cells. CAFs are highly heterogeneous and play crucial roles in lung cancer. This review highlights recent advances in the understanding of CAFs in lung cancer, focusing on their heterogeneity and functions in tumorigenesis, progression, angiogenesis, invasion, metastasis, therapy resistance, tumor immune suppression, and targeted therapy responses. Additionally, we explore the underlying mechanisms and the potential of CAFs as a target in the development of innovative therapies for lung cancer.

Tuberculosis (TB) significantly increases the risk of developing chronic obstructive pulmonary disease (COPD), positioning TB-associated COPD (TB-COPD) as a distinct category within the spectrum of respiratory diseases prevalent, especially in low- and middle-income countries. This condition results from the body's immune response to TB, leading to prolonged inflammation and consequent persistent lung damage. Diagnostic approaches, particularly post-bronchodilator spirometry, are vital for identifying airflow obstruction and confirming TB-COPD. Furthermore, exploring potential biomarkers is crucial for a deeper insight into the pathogenesis of TB-COPD and the improvement of treatment strategies. Currently, this condition is primarily managed using inhaled bronchodilators, with cautious use of inhaled corticosteroids advised owing to the increased risk of developing TB. This review delves into the epidemiology, clinical manifestations, pulmonary function, and imaging characteristics of TB-COPD, scrutinizing current and prospective biomarkers and therapeutic strategies. Furthermore, it underscores the necessity for focused research to bridge the knowledge and treatment gaps in this complex condition.