Potential Impact of Diabetes and Obesity on Alveolar Type 2 (AT2)-Lipofibroblast (LIF) Interactions After COVID-19 Infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new emerging respiratory virus, caused evolving pneumonia outbreak around the world. In SARS-Cov-2 infected patients, diabetes mellitus (DM) and obesity are two metabolic diseases associated with higher severity of SARS-CoV-2 related complications, characterized by acute lung injury requiring assisted ventilation as well as fibrosis development in surviving patients. Different factors are potentially responsible for this exacerbated response to SARS-CoV-2 infection. In patients with DM, base-line increase in inflammation and oxidative stress represent preexisting risk factors for virus-induced damages. Such factors are also likely to be found in obese patients. In addition, it has been proposed that massive injury to the alveolar epithelial type 2 (AT2) cells, which express the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), leads to the activation of their stromal niches represented by the Lipofibroblasts (LIF). LIF are instrumental in maintaining the self-renewal of AT2 stem cells. LIF have been proposed to transdifferentiate into Myofibroblast (MYF) following injury to AT2 cells, thereby contributing to fibrosis. We hypothesized that LIF’s activity could be impacted by DM or obesity in an age- and gender-dependent manner, rendering them more prone to transition toward the profibrotic MYF status in the context of severe COVID-19 pneumonia. Understanding the cumulative effects of DM and/or obesity in the context of SARS-CoV-2 infection at the cellular level will be crucial for efficient therapeutic solutions.

Cellular and Molecular Mechanism of Pulmonary Fibrosis Post-COVID-19: Focus on Galectin-1, -3, -8, -9

“…Pulmonary lipofibroblasts, a special type of interstitial fibroblasts which contain typical lipid droplets, are located nearb type 2 alveolar epithelial cells to transfer triglyceride to these epithelial cells [ 48 , 49 ]. Lipofibroblasts interplay with resident lung mesenchymal cells proposed to represent the mesenchymal niche for type 2 alveolar epithelial stem cells [ 50 ]. They are heterogeneous populations that expressed different markers, such as platelet-derived growth factor receptor alpha (Pdgfrα Pos ), Axin2 Pos , and fibroblast growth factor 10 (Fgf10 Pos ) [ 50 ].…”

“…Lipofibroblasts interplay with resident lung mesenchymal cells proposed to represent the mesenchymal niche for type 2 alveolar epithelial stem cells [ 50 ]. They are heterogeneous populations that expressed different markers, such as platelet-derived growth factor receptor alpha (Pdgfrα Pos ), Axin2 Pos , and fibroblast growth factor 10 (Fgf10 Pos ) [ 50 ].…”

“…Lipofibroblasts may have an important role in the post-COVID-19 effects, especially in obese or diabetic patients [ 50 ]. In response to various stimuli, such as hyperoxia and infection [ 51 ], pulmonary lipofibroblasts can trans-differentiate from myofibroblasts and contribute to pulmonary fibrosis [ 52 ].…”

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity

“…Due to chronic low-grade inflammatory preconditioning, adipose tissue is also a source of many pro-inflammatory mediators and adipokines that may enhance the characteristic cytokine storm, lastly seen in COVID-19 infection [12]. Recent evidence has suggested that dysfunctional lipofibroblasts in obesity may play a key role in the pulmonary fibrosis induced by viral infections [59]. Lipofibroblast activity is regulated by lung epithelial cells that express high levels of angiotensin-converting enzyme 2 (ACE-2), a surface protein that can be used as an entry receptor by several respiratory viruses [60].…”

“…As previously discussed, obesity has a negative impact on lipofibroblast function, rendering the cells more prone to profibrotic transition. Based on these findings, it has been hypothesised that obesity could be a negative prognostic factor in patients with COVID-19, as ectopic fat deposition in the lungs of obese subjects could lead to lipofibroblast dysfunction, promoting lung fibrosis [59].…”