Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 10¹⁰ particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 10¹¹ particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.

Coronavirus disease 2019 (COVID-19) has so far infected hundreds of million individuals, with several million deaths worldwide. The lack of understanding of the disease pathophysiology and the host’s immune response has resulted in this rapid spread of the disease on a global scale. In this respect, we employed UPLC-MS to compare the metabolites in the serum from COVID-19-positive patients and COVID-19-recovered subjects to determine the metabolic changes responsible for an infection. Our investigations revealed significant increase in the levels of serum phospholipids including sphingomyelins, phosphatidylcholines and arachidonic acid in the serum of COVID-19-positive patients as compared to COVID-19-recovered individuals. We further show increased levels of tryptophan and its metabolites in the serum of COVID-19-positive patients thus emphasizing the role of tryptophan metabolism in the disease pathogenesis of COVID-19. Future studies are required to determine the changes in the lipid and tryptophan metabolism at various stages of COVID-19 disease development, progression and recovery to better understand the host–pathogen interaction and the long-term effects of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection in humans.

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16^INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12–14 months) and old (17–20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions.

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and senotherapeutics in the field of lung biology and disease e.g. stages of COPD and IPF, which aim to mitigate the detrimental effects of senescent cell (SnC) accumulation. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in senescent cells (SnCs), and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. It discusses various classes of senolytic and senomorphic agents and their deliveries, including natural products (e.g., quercetin, fisetin, resveratrol), repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin), and innovative approaches like HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs. Preclinical evidence and emerging data from early-phase human clinical trials, particularly with the combinatorial approach of Dasatinib & Quercetin (D+Q) and fisetin, demonstrate the therapeutic promise of these interventions in improving tissue function, alleviating LARDs, and potentially extending healthspan. The review also highlighted significant challenges, including SnC heterogeneity, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions.

The effects of commercially available brands of common e-liquid humectants – propylene glycol (PG) and vegetable glycerin (VG) are not known. This study evaluates the toxicities of commercially available PG and VG mixtures compared to their analytically pure grade chemicals. The pH and the viscosity of 50:50 PG/VG mixtures from four different commercially available brands and a pure chemical mixture were measured. Commercially available brands of PG/VG generally had higher pH (up to ∼6.25) and viscosity values (up to 16.4 %) than the pure chemical mixture (pH = 5.5; viscosity = 12.9 %). GC-MS spectra provide evidence of impurities in commercially available PG, but not VG liquids when compared to pure chemicals. While we observe variation in the level of acellular reactive oxygen species generated by commercial mixtures as compared to the pure chemical, the protein carbonylation levels were comparable for both the mixtures, thus indicating variation in the nature of the oxygen species generated upon aerosolization. No noticeable change was observed upon studying the human monocytic U937 cellular responses upon treatment with sub-toxic concentrations of PG/VG mixtures; however, a decrease in the basal IL-8 production was observed at higher concentrations (1 %) of PG/VG treatment. The commercially available PG/VG mixtures show comparable oxidative and biological effects to the pure chemical. However, GC-MS data identified impurities which may explain our observation of a variable ROS profile in each PG/VG mixture. Future work on the brand-specific toxicity of PG/VG or its usage is warranted to inform regulatory guidelines for e-cigarettes.