This study aimed to identify significant gene expression profiles of the human lung epithelial cells caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We performed a comparative genomic analysis to show genomic observations between SARS-CoV and SARS-CoV-2. A phylogenetic tree has been carried for genomic analysis that confirmed the genomic variance between SARS-CoV and SARS-CoV-2. Transcriptomic analyses have been performed for SARS-CoV-2 infection responses and pulmonary arterial hypertension (PAH) patients’ lungs as a number of patients have been identified who faced PAH after being diagnosed with coronavirus disease 2019 (COVID-19). Gene expression profiling showed significant expression levels for SARS-CoV-2 infection responses to human lung epithelial cells and PAH lungs as well. Differentially expressed genes identification and integration showed concordant genes (SAA2, S100A9, S100A8, SAA1, S100A12 and EDN1) for both SARS-CoV-2 and PAH samples, including S100A9 and S100A8 genes that showed significant interaction in the protein–protein interactions network. Extensive analyses of gene ontology and signaling pathways identification provided evidence of inflammatory responses regarding SARS-CoV-2 infections. The altered signaling and ontology pathways that have emerged from this research may influence the development of effective drugs, especially for the people with preexisting conditions. Identification of regulatory biomolecules revealed the presence of active promoter gene of SARS-CoV-2 in Transferrin-micro Ribonucleic acid (TF-miRNA) co-regulatory network. Predictive drug analyses provided concordant drug compounds that are associated with SARS-CoV-2 infection responses and PAH lung samples, and these compounds showed significant immune response against the RNA viruses like SARS-CoV-2, which is beneficial in therapeutic development in the COVID-19 pandemic.