Interaction of Biochemical Processes between Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Arterial Hypertension (PAH), and Coronavirus Disease 2019 (COVID-19)

Coronavirus disease 2019 (COVID-19) is the infectious respiratory illness brought on by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite extensive precautions, COVID-19 has resulted in unfathomable losses throughout the world. With a genomic sequence of 29,903 positive-sense singlestranded RNA (ss-RNA) nucleotides and a very high mutation rate, SARS-CoV-2 is a member of the coronavirus genus (Yi et al. 2021). SARS-CoV-2 attaches to host cells’ angiotensin-converting enzyme 2 (ACE2) receptor. S protein is a crucial protein that mediates virus invasion of host cells, and, therefore, it is a key target for antibody production. Currently, SARS-CoV-2 mutations in the receptor binding domain (RBD), where the S protein interacts with ACE2, pose significant difficulties in controlling and preventing epidemics. Although some people are asymptomatic, COVID-19 symptoms include fever, cough, dyspnea, and loss of taste or smell. Symptomatic patients can be divided into mild and severe cases; mild ones with common coldlike discomfort and severe ones with life-threatening sudden acute viral pneumonia.

The information links preexisting illnesses such as chronic obstructive pulmonary disease (COPD), diabetes, and cardiovascular disease to severe symptoms and higher death after COVID-19 infection (Aghagoli et al. 2020; Alqahtani et al. 2020; Huang et al. 2020; Wu et al. 2020). Given the lung damage caused by SARS-CoV-2, we are concerned that underlying chronic respiratory disease may increase the risk of developing COVID-19. Patients with COPD have higher levels of ACE2 in their airways, which may increase their risk for severe COVID-19 infection (Leung et al. 2020). The development of COVID-19 and greater susceptibility to viral infection may also be influenced by interferon production and other innate immune responses in COPD. Patients with COVID-19 who are hospitalized for COPD should get cautious observation.

Pulmonary hypertension and pulmonary arteriolar vascular remodeling are two signs of pulmonary arterial hypertension (PAH) (Zhang et al. 2020b). Patients with severe COVID-19 had 20% higher PAH levels (Mishra et al. 2020). Transthoracic echocardiography reportedly revealed a higher incidence of PAH in 91 patients with moderate COVID-19 infection who were treated and released (Tudoran et al. 2021). This study hypothesized that the severity of PAH, a frequent side effect of COVID-19 infection, appears to be correlated with the degree of initial lung injury and inflammatory response. There is an assumption that the number of PAH found in COVID-19 patients did not increase in the hardest-hit areas; however, it is also assumed that areas struck by the pandemic did not show an increase in the number of PAH among COVID-19 patients (Farha and Heresi 2020). The ACE2 prevalence is downregulated in PAH (Zhang et al. 2018), although whether this is advantageous or detrimental to COVID-19 patients is unclear.

This research sought to identify the biochemical processes underlying COVID-19, COPD, PAH, and their interactions. The GSE147507, GSE106986, and GSE15197 were selected from the GEO database, representing COVID-19, COPD, and PAH. The data set was first screened for DEGs to identify co-DEGs among the three diseases. In genome-based expression investigations, these co-DEGs were employed for pathway and enrichment analyses to comprehend biological processes. Co-DEGs were examined using the PPI network, and the regulatory and interaction networks between TF and miRNA. Finally, candidate drugs were selected.

COVID-19 has made the world face a series of challenges, and this study has combined COVID-19, COPD, and PAH. It is worth exploring a series of complications caused by COVID-19. Research on miRNA-targeted drugs and vaccines has been carried out worldwide, and further analysis of TFs and miRNAs listed in this paper may unearth additional drugs.

COVID-19 can cause severe illness in people with COPD, which is concerning. SARS-CoV-2 enters host cells and binds to ACE2 to cause COVID-19 (Bhuiyan et al. 2018; Saheb Sharif-Askari et al. 2020). A study investigated airway ACE2 gene expression levels in patients with and without COPD, which manifested that ACE2 expression was significantly increased in the former group. Additionally, the gene expression level of ACE2 was found to be negatively correlated with individual forced expiratory volume 1st (FEV1) (Gholaminejad et al. 2021). Although upregulating of ACE2 may help protect against acute lung injury, coronaviruses use this receptor to enter epithelial cells, thereby increasing their chances of infecting the host. The pathogenesis and complications of COVID-19 are well documented, but there are few reports on PAH. Deng et al. (2020) found that the incidence of PAH in patients with severe COVID-19 was significantly higher than in those without severe COVID-19, but they did not describe the specific situation of PAH and its relationship with the clinic, and did not rule out PAH caused by previous diseases, pulmonary embolism or other causes. Patients with COVID-19 may experience pulmonary vasoconstriction and impaired lung function due to hypoxemia and inflammation brought on by pathological lung alterations (Vicenzi et al. 2020), leading to PAH. ACE2 can convert angiotensin ii into angiotensin to play a vasodilator role (Tang et al. 202) and effectively reduce pulmonary vascular resistance, thus, delaying or reducing the occurrence of PAH. SARS-CoV-2, on the other hand, binds to ACE2 and suppresses its expression by endocytosis and proteolytic enzyme cleavage (Ovali et al. 2020). More research is required to determine whether PAH in severe and critical COVID-19 patients is brought on by the depletion of ACE2 in lung tissue.

This study’s goal was to examine COVID-19, COPD, and PAH crossover using bioinformatics-related methods. As putative molecular targets of COVID-19, 11 common DEGs were discovered from the GSE147507, GSE106986, and GSE15197 databases. Drug candidate screening, GO analysis, pathway analysis, PPI network, TF-gene interaction, and TF-miRNA-gene synergy network were also done. The BP, RALBP1, and PGF genes appeared many times, and they were mostly enriched in processes that positively regulated protein modification and phosphorylation. A more significant part of COVID-19’s quick infection is the phosphorylation modification. On the Vero E6 cell model infected with SARS-CoV-2, the viral protein concentration began to increase 8 hours after infection, and their host protein abundance changed only slightly within 24 hours. Protein phosphorylation, however, was drastically altered. Furthermore, some viral proteins could be phosphorylated according to the results of phosphotomics. Sequence analysis revealed that host CK2, CDK, and PKC are upstream kinases leading to the phosphorylation of these viral proteins, which might contribute to virus infection. At the host level, by cluster analysis of phosphorylation sites and kinase prediction, it was found that the activities of P38 MAPK, CK2, CAMK2G, and other kinases were up-regulated. In contrast, CDK, AKT, and Rho family kinase activities were down-regulated (Aghagoli et al. 2020). ERK1/2, p38, and eIF4E were considerably more phosphorylated in the platelets of COVID-19 individuals in the ICU ward, activating the MAPK pathway (Manne et al. 2020). Patients recovered from COVID-19 showed significant inhibition of the MAPK pathways (FOS, JUN, JunB, and DUSP1), indicating that inhibition of these pathways might be a sign of restoration (Zhang et al. 2020a). Compared with non-smokers, COPD patients have increased p38 MAPK activity in alveolar wall macrophages and other cells (Banerjee et al. 2012), p38 MAPK inhibitors may help target airway inflammation by reducing cytokine production by alveolar macrophages. Additionally, MAPK activation is positively associated with PAH occurrence and development (Wei et al. 2019). It suggests that SARS-CoV-2 infection can encourage the activation of P38 MAPK and worsen COPD and PAH patients’ conditions. Vascular endothelial growth factor receptor binding was the MF term that was statistically the most significant. Vascular endothelial growth factor, which increases vascular permeability, results in tissue hypoxia by causing pulmonary vascular leakage, plasma extravasation, and pulmonary edema (Kaner et al. 2000). Thus, improving oxygen perfusion, the anti-inflammatory response, and reducing clinical symptoms in COVID-19 patients, can be achieved by limiting the signal transduction mediated by the vascular endothelial growth factor and its receptor (Pang et al. 2012). Some researchers claim that SARS-CoV-2 infection can alter the extracellular milieu in the lung, suggesting a potential pathophysiologic mechanism (Leng et al. 2020). Activation of the RAS signaling system, oxidative stress and cell death, cytokine storm, and endothelial dysfunction is hypothesized to be the four pathways that lead to COVID-19. One important anti-COVID-19 mechanism of NSAIDs is the inhibition of RAS signaling, which inhibits tissue and/or cellular proinflammatory stimuli (Oh et al. 2021).

TF is a crucial regulator at the transcriptional level, and miRNA primarily controls gene expression at the post-transcriptional point. As a result of their interaction, target gene expression is also synergistically regulated, making the gene expression regulatory network more accurate. As our results show, the degree value in the network of TF-gene interactions for RALBP1 and ABLIM3 is 20, and they often interact with other TF genes. IRF1, one of these TFs, had a degree value of 3 in the network of TF-gene interactions and significantly interacted with co-DEGs. Transcriptional factors such as IRF regulate the expression of genes that encode IFN. A high expression of antiviral genes has been found in bat cells and tissues; often, these are associated with IFNα signaling, and IRF contributes to the expression of IFN-I ligands (Irving et al. 2020). More significantly, IFN-I signaling induces explicitly the transcription factor IRF1, which stimulates the transcription of proinflammatory cytokine genes (Lazear et al. 2019). Additionally, Rusmini et al. (2021) discovered that COVID-19 was positively related to an intronic mutation of IRF1 (rs17622656), which may result in decreased carnitine absorption and impaired immune response to SARS-CoV-2.

The TF-miRNA co-regulation network contained 68 TF genes and 94 miRNAs. The majority of these miRNAs are linked to cancer tissue and contribute to various cancers in people, particularly lung cancer. In TFs, the most substantial interactions are NFKB1 and JUN, with values of 4 and 3, respectively. Among the miRNAs, the strongest interactions are has-miR-506 and hsa-miR-942, both with a degree value of 2. Patients with COVID-19 experience a cytokine storm as a result of TNF-induced NFKB1 activation. CD4⁺ T cells are involved in viral infection. Wen et al. (2020) discovered that the expression of the Jun gene (inflammatory response) was high in CD4⁺ T cells from COVID-19 survivors. Anti-inflammatory genes linked to CD4⁺ T cells were found to be downregulated in COVID-19 individuals compared to healthy controls. Individuals with mild to moderate COPD and those without COPD had higher levels of c-JUN in their epithelial cells than patients with severe or very severe COPD (Reddy et al. 2012). Lack of c-JUN increases the severity of lymphocyte infiltration and smoking-induced lung inflammation (Hogg et al. 2004). miR-506-3p overexpression prevents cancer cell proliferation, migration, and invasion while its expression is downregulated in non-small cell lung cancer tissues and cells (Guo et al. 2017.).

COVID-19 is currently not treated with a specific drug, so reusing existing drugs is considered a critical step toward a faster recovery (Yan et al. 2021). Some antiviral activity against SARS-CoV-2 has been demonstrated for chloroquine, remdesivir, nitazoxanide, interferon, lopinavir-ritonavir, ribavirin, favipiravir, hydroxychloroquine, camostat, and convalescent plasma carrying antibodies (Beigel et al. 2019; Cunningham et al. 2020; Dong et al. 2020; Li et al. 2020; Sheahan et al. 2020; Verma et al. 2020). Based on 10 co-EDGs, the DSigDB database recommends the top 10 drug candidates. Most COVID-19 patients are known to have a fever while in the hospital. It is recommended that COVID-19 patients use acetaminophen instead of NSAIDs as a symptom reliever (Park et al. 2021).