Angiotensin-Converting Enzyme 2 (ACE2), Transmembrane Peptidase Serine 2 (TMPRSS2), and Furin Expression Increases in the Lungs of Patients with Idiopathic Pulmonary Fibrosis (IPF) and Lymphangioleiomyomatosis (LAM): Implications for SARS-CoV-2 (COVID-19) Infections

Abstract

We previously reported higher ACE2 levels in smokers and patients with COPD. The current study investigates if patients with interstitial lung diseases (ILDs) such as IPF and LAM have elevated ACE2, TMPRSS2, and Furin levels, increasing their risk for SARS-CoV-2 infection and development of COVID-19. Surgically resected lung tissue from IPF, LAM patients, and healthy controls (HC) was immunostained for ACE2, TMPRSS2, and Furin. Percentage ACE2, TMPRSS2, and Furin expression was measured in small airway epithelium (SAE) and alveolar areas using computer-assisted Image-Pro Plus 7.0 software. IPF and LAM tissue was also immunostained for myofibroblast marker α-smooth muscle actin (α-SMA) and growth factor transforming growth factor beta1 (TGF-β1). Compared to HC, ACE2, TMPRSS2 and Furin expression were significantly upregulated in the SAE of IPF (p < 0.01) and LAM (p < 0.001) patients, and in the alveolar areas of IPF (p < 0.001) and LAM (p < 0.01). There was a significant positive correlation between smoking history and ACE2 expression in the IPF cohort for SAE (r = 0.812, p < 0.05) and alveolar areas (r = 0.941, p < 0.01). This, to our knowledge, is the first study to compare ACE2, TMPRSS2, and Furin expression in patients with IPF and LAM compared to HC. Descriptive images show that α-SMA and TGF-β1 increase in the IPF and LAM tissue. Our data suggests that patients with ILDs are at a higher risk of developing severe COVID-19 infection and post-COVID-19 interstitial pulmonary fibrosis. Growth factors secreted by the myofibroblasts, and surrounding tissue could further affect COVID-19 adhesion proteins/cofactors and post-COVID-19 interstitial pulmonary fibrosis. Smoking seems to be the major driving factor in patients with IPF.

Platelet Activating Factor Receptor and Intercellular Adhesion Molecule–1 Expression Increases in the Small Airway Epithelium and Parenchyma of Patients with Idiopathic Pulmonary Fibrosis: Implications for Microbial Pathogenesis

“…Furthermore, our research group previously reported that ACE2, Furin and Transmembrane protease serine 2 (TMPRSS2) receptors are upregulated in IPF facilitating SARS-CoV-2 infection [19]. We have reported similar findings in smokers and patients with COPD.…”

“…A synergy between bacteria and virus has been documented, detailing that it causes superinfections that exacerbate IPF progression, reducing lung function and lowering the survival rate compared to uninfected patients [15]. Similarly, SARS-CoV-2 receptor angiotensinconverting enzyme 2 (ACE2) has been shown to upregulate in patients with IPF, increasing their susceptibility to COVID-19 [15,19]. With this knowledge, we wanted to investigate the presence of other potential microbial receptors, such as platelet-activating factor receptor (PAFR) and intracellular adhesion molecule-1 (ICAM-1), and their possible involvement in microbial entry into host cells [20][21][22][23].…”

Single cell meta-analysis of EndMT and EMT state in COVID-19

“…They found TGF-β1 and α-smooth muscle actin (myofibroblast marker) are in similar areas as COVID-19 markers. They suggest that myofibroblasts and surrounding tissue secrete growth factors which could further affect COVID-19 adhesion proteins/cofactors and post-COVID-19 interstitial pulmonary fibrosis ( 37 ). Our study confirms that entry factors are negatively correlated with early EndMT cell fraction and are positively correlated with fibroblasts.…”

Sex Steroids Effects on Asthma: A Network Perspective of Immune and Airway Cells

“…Some hypotheses, including ours, implicate sex steroids in differential effects of COVID-19. For example, we observed higher baseline expression of the ACE2 receptor in the ASM in males compared to females [ 208 , 215 ]. More importantly, when age-matched male and female ASM cells were exposed to physiological concentrations of the sex steroids independently, testosterone increased ACE2 expression, whereas estrogen downregulated ACE2 in ASM [ 208 ].…”