Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis

Abstract

Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.

The Role of Smoking and Nicotine in the Transmission and Pathogenesis of COVID-19

“…The ratio of AT 1 R to AT 2 R increased five to six fold in bronchiole areas with enhanced fibrosis, which were associated with diminished lung function in COPD patients (Bullock et al, 2001). A recent study also showed that sub-chronic e-Cig exposure enhances lung inflammation and ACE2 expression which were shown to be mediated by α7 nAChRs (Wang et al, 2020c disorders in association with COVID-19 infection (Maremanda et al, 2020). These results indicate that smokers and/or vapers may have an increased risk of COVID-19 related complications which can aggravate disease severity and treatment outcome.…”

Distinct exosomal miRNA profiles from BALF and lung tissue from COPD and IPF patients

“…Likewise, the lung samples were procured from three sources; (a) commercially available resource for procurement of human tissue and organ-NDRI (National Disease Research Interchange), (b) NHLBI-funded bio-specimen repository-LTRC (Lung Tissue Research Consortium), and (c) Department of Medicine and Pathology at the University of Helsinki Hospital, Finland as reported previously (31, 32).…”

Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension

“…Heat shock protein Involved in pulmonary disease as differential expression gene (Maremanda et al, 2020).…”

“…Consistent with our findings, ANGPT2 was upregulated in several inflammatory diseases and took part in the direct regulation of inflammationrelated signal pathways in PAH (Zhong et al, 2018). Differential expression of HSPD1, involved in mitochondrial biogenesis, was noted in patients suffering from pulmonary diseases compared with normal controls (Maremanda et al, 2020). Interaction of HSPH1 with STAT3 may enhance its phosphorylation, which exacerbated pulmonary inflammation in acute lung injury, though there is no such report relating to PAH (Liang et al, 2020).…”

“…However, there are limited studies providing PAH-associated gene expression profiles, and a number of studies implying that there may be an extraordinary significance of investigating this type of clinical molecular biomarkers and elucidating the fundamental mechanisms involved in PAH. This may be useful in developing a new scientific-based diagnosis modality and performing targeted therapy in patients with PAH more precisely (Farhadi et al, 2017;Sullivan and Kass, 2019;Ma et al, 2020;Maremanda et al, 2020).…”