Organoid techniques and mouse models of lung injury to evaluate the effect of hydroxychloroquine on lung epithelial regeneration

The December 2019 outbreak of coronavirus disease (COVID-19) in December 2019 affected populations in more than 200 countries and territories around the world
.
COVID-19 is clinically classified into the following grades based on their severity: mild to moderate, severe, and critical (respiratory failure).

Common symptoms include fever, cough, and muscle pain, and patients often present with the following pulmonary histopathologic features: pulmonary epithelial injury, hyaline membrane formation, and diffuse inflammatory infiltrates
.

Epithelial stem/progenitor cells, including club cells and type 2 alveolar (AT2) cells, are located in the intralobar conduction airways and alveoli of the human lung, respectively
.
When the lung epithelium is damaged, these cells can renew themselves to regenerate and repair the lung epithelium
.
Once the repair is complete, the structure and function of the lung will be restored
.
Club cells produce cilia cells and goblet cells by proliferation and differentiation, while AT2 cells can differentiate into AT1 cells, which are necessary for
gas exchange.
SARS-CoV-2 invades cells through its spike protein, binding
to angiotensin-converting enzyme 2 (ACE2) receptors.
Since ACE2 receptors are expressed on the surface of club cells and AT2 cells, these two epithelial progenitor cells can be targeted and disrupted
by SARS-CoV-2.
Reduced lung progenitor cell pool may impair the regenerative capacity of the epithelium and slow the recovery
of the epithelial barrier.
In line with this, lung damage in COVID-19 patients caused by SARS-CoV-2 infection is thought to last a long time
.
Therefore, patients with COVID-19 should be screened for clinical medications prescribed to avoid secondary damage to lung epithelial progenitor cells to reduce the progression
of pulmonary fibrosis.

Isolation of lung epithelial progenitor cells and organoid culture:

To date, there is no effective drug treatment for COVID-19 patients
.
Several potential anti-SARS-CoV-2 drug candidates have been proposed and clinically tested
.
For example, remdesivir can block the viral life cycle by inhibiting viral
RNA-dependent RNA polymerase.
However, its efficacy in the treatment of COVID-19 remains controversial
.
Hydroxychloroquine (HCQ) can inhibit the glycosylation of host receptors and increase the pH of endosomes to prevent viruses from entering cells
.
It exerts an antiviral effect
by regulating activated immune cells.
Some studies have shown that HCQ treatment has beneficial effects for people with COVID-19, such as increasing rates of improvement in pneumonia, reducing fever more quickly, and reducing mortality
.
In this study, in vitro organoid cultures and mouse models of lung epithelial injury were used to evaluate the effect of
HCQ on club and AT2 cell regeneration.

Hydroxychloroquine (HCQ) has no effect on regeneration of mouse club cells during naphthalene-induced airway epithelial injury:

Hydroxychloroquine (HCQ) has no effect on the regeneration of AT2 during bleomycin (BLM)-induced alveolar epithelial injury:

Combining in vitro and in vivo findings, the investigators concluded that HCQ had little to no impact on the regenerative capacity of lung epithelial stem/progenitor cells, reducing concerns about
potential fibrosis progression in recovered COVID-19 patients receiving HCQ.

References: Zhao F, Wang J, Wang Q, Hou Z, Zhang Y, Li X, Wu Q, Chen H.
Organoid technology and lung injury mouse models evaluating effects of hydroxychloroquine on lung epithelial regeneration.
Exp Anim.
2022 Aug 5; 71(3):316-328.
doi: 10.
1538/expanim.
21-0168.
Epub 2022 Feb 22.
PMID: 35197405; PMCID: PMC9388344.