Targeting eosinophils in chronic respiratory diseases using nanotechnology-based drug delivery

Asthma, COPD, COVID-19, EGPA, Lung cancer, and Pneumonia are major chronic respiratory diseases (or CRDs) affecting millions worldwide and account for substantial morbidity and mortality. These CRDs are irreversible diseases that affect different parts of the respiratory system, imposing a considerable burden on different socioeconomic classes. All these CRDs have been linked to increased eosinophils in the lungs. Eosinophils are essential immune mediators that contribute to tissue homeostasis and the pathophysiology of various diseases. Interestingly, elevated eosinophil level is associated with cellular processes that regulate airway hyperresponsiveness, airway remodeling, mucus hypersecretion, and inflammation in the lung. Therefore, eosinophil is considered the therapeutic target in eosinophil-mediated lung diseases. Although, conventional medicines like antibiotics, antiinflammatory drugs, and bronchodilators are available to prevent CRDs. But the development of resistance to these therapeutic agents after long-term usage remains a challenge. However, progressive development in nanotechnology has unveiled the targeted nanocarrier approach that can significantly improve the pharmacokinetics of a therapeutic drug. The potential of the nanocarrier system can be specifically targeted on eosinophils and their associated components to obtain promising results in the pharmacotherapy of CRDs. This review intends to provide knowledge about eosinophils and their role in CRDs. Moreover, it also discusses nanocarrier drug delivery systems for the targeted treatment of CRDs.

Increased expression of angiotensinconverting enzyme 2 (ACE2), TMPRSS2 and furin in idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM) patients' lung tissue: Implications for COVID -19

Background and Aims: Patients with chronic lung disease are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to COVID-19. ACE2 is the main receptor for SARS-CoV-2 attachment. Our previous study reported higher ACE2 levels in smokers and COPD patients. Current study investigates if patients with interstitial lung diseases (ILDs) such as IPF and LAM have elevated levels of ACE2, transmembrane peptidase serine 2 (TMPRSS2) and Furin, increasing their risk for SARS-CoV-2 infection. Methods: Surgically resected lung tissue from IPF, LAM patients and normal controls (NC) was immunostained for ACE2, TMPRSS2 and Furin. Percentage ACE2 expression was measured in small airway (SA) epithelium and alveolar areas. Analysis was done using computer-assisted Image- ProPlus 7.0 software. Results: Compared to NC, the percentage ACE2 expression significantly increased in the SA epithelium of IPF (p<0.01), LAM (p<0.001) and in alveolar areas of IPF (p<0.001), LAM (p<0.001). We also observed elevated TMPRSS2 and Furin expression in the same lung tissue areas of IPF and LAM against NC. There was significant positive correlation between smoking history and ACE2 expression in the IPF for SA epithelium (r=0.81, p<0.05) and alveolar areas (r=0.94, p<0.01). Conclusions: This study has investigated the ACE2, TMPRSS2, and Furin in resected lung tissue of IPF and LAM, which suggests that people with ILDs are at higher risk of developing severe COVID-19 infection. To further understand and provide potential therapeutic targets for ILDs, we need to explore other cell types such as type II pneumocytes, alveolar macrophages and endothelial cells.

Electronic Cigarette Aerosol Condensate Increases ACE2 Expression on Human Airway Epithelial Cells: Implications for SARS-CoV-2 (COVID-19)

RATIONALE Tobacco smoking, via nicotine receptor (α7 nAChR), increases risk for the susceptibility to infection from SARS-CoV-2 via increased expression of ACE2 in the lung. Given the modifiable nature and high risk of electronic cigarettes, with potential to deliver toxic concentrations of nicotine, we investigated if electronic cigarettes are also a danger in relation to COVID-19. We investigated the cytotoxicity of electronic cigarette exposure and whether flavored vaping has the potential to increase susceptibility to SARS-CoV-2 infection in large and small airway epithelial cells through the upregulation of ACE2. METHODS We exposed bronchial epithelial (BEAS-2B) and primary human small airway epithelial (SAEC) cells to e-cigarette aerosol condensates produced from propylene glycol/vegetable glycerin (PG/VG) or locally bought [Juicius Maximus, watermelon flavor (WM)] e-liquid (± added nicotine), and cigarette smoke extract (CSE). Aerosols were produced from a Drag2 e-cigarette device (Vapoo) operated at 60W, with a 0.4Ω U2 dual coil (Vapoo), and condensates were collected in flasks over dry ice with the aid of a peristaltic pump, then stored at -80°C. We investigated if e-cigarette exposure, alike cigarette smoke, increases the expression of ACE2 in lung epithelial cells. Cytotoxicity (CCK-8), membrane integrity by lactate dehydrogenase (LDH) release, and ACE2 protein expression (immunofluorescence) were measured for both 4- and 24-hour treatments;ACE2 gene expression was measured using qPCR for 4- hour treatment only. RESULTSFor both BEAS-2B cells and SAECs, nicotine-free condensates and higher concentrations of nicotine-containing condensates were highly cytotoxic (PG/VG, JM ± nicotine(60mg);∗∗∗p<0.0001, ∗∗∗p<0.001). Higher LDH release was seen in BEAS-2B cells treated for 24 hours with higher concentrations of nicotine-containing condensates (PG/VG, JM + nicotine(18 or 60mg): ∗∗∗∗p<0.0001, ∗∗p<0.01) indicating that the membrane integrity was disturbed. Cells appear to be under significant distress. Small increases in LDH were also seen with 4 hours treatment (∗∗∗∗p<0.0001, ∗∗∗p<0.001, ∗∗p<0.01∗p<0.05). ACE2 protein expression was observably increased in all treatments compared to media controls, particularly for 24 hours exposures. ACE2 gene expression was significantly increased in cells exposed to WM + 60mg/mL nicotine (∗∗p<0.1) and cigarette smoke extract (∗∗∗∗p<0.0001) compared with media controls. CONCLUSIONS Our study confirms that electronic cigarettes condensates are highly cytotoxic. Data also suggests that vaping can result in an increase in lung ACE2 expression as we have shown for tobacco smoking. The health care community needs to stay alert;vaping and smoking are avoidable risk factors for SARS-CoV-2 infection and should be avoided during and post- the COVID-19 pandemic.

Potential diagnostics and therapeutic approaches in COVID-19.

The most important aspect of controlling COVID-19 is its timely diagnosis. Molecular diagnostic tests target the detection of any of the following markers such as the specific region of the viral genome, certain enzyme, RNA-dependent RNA polymerase, the structural proteins such as surface spike glycoprotein, nucleocapsid protein, envelope protein, or membrane protein of SARS-CoV-2. This review highlights the underlying mechanisms, advancements, and clinical limitations for each of the diagnostic techniques authorized by the Food and Drug Administration (USA). Significance of diagnosis triaging, information on specimen collection, safety considerations while handling, transport, and storage of samples have been highlighted to make medical and research community more informed so that better clinical strategies are developed. We have discussed here the clinical manifestations and hospital outcomes along with the underlying mechanisms for several drugs administered to COVID-19 prophylaxis. In addition to favourable clinical outcomes, the challenges, and the future directions of management of COVOD-19 are highlighted. Having a comprehensive knowledge of the diagnostic approaches of SARS-CoV-2, and its pathogenesis will be of great value in designing a long-term strategy to tackle COVID-19.