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Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify proteomic footprints that could be potentially useful in predicting mortality in stable COPD patients. Plasma samples from 40 patients were subjected to both blind (liquid chromatography–mass spectrometry) and hypothesis-driven (multiplex immunoassays) proteomic analyses supported by artificial intelligence (AI) before a 4-year clinical follow-up. Among the 34 patients whose survival status was confirmed (mean age 69 ± 9 years, 29.5% women, FEV1 42 ± 15.3% ref.), 32% were dead in the fourth year. The analysis identified 363 proteins/peptides, with 31 showing significant differences between the survivors and non-survivors. These proteins predominantly belonged to different aspects of the immune response (12 proteins), hemostasis (9), and proinflammatory cytokines (5). The predictive modeling achieved excellent accuracy for mortality (90%) but a weaker performance for days of survival (Q2 0.18), improving mildly with AI-mediated blind selection of proteins (accuracy of 95%, Q2 of 0.52). Further stratification by protein groups highlighted the predictive value for mortality of either hemostasis or pro-inflammatory markers alone (accuracies of 95 and 89%, respectively). Therefore, stable COPD patients’ proteomic footprints can effectively forecast 4-year mortality, emphasizing the role of inflammatory, immune, and cardiovascular events. Future applications may enhance the prognostic precision and guide preventive interventions.

The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year’s exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18–60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8+HLA-DR+ and CD8+CD28− T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8+CD28− T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5 × 10−4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10−3 to 3.77 × 10−8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.