SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation, A Dynamical Mathematical Model

In the present work we propose a dynamical mathematical model of the lung cells inflammation process in response to SARS-CoV-2 infection. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 also increases above the threshold value of 7 pg mL−1 s−1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5. To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 is effectively a central node underlying the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. Nsp5 seems to be the switch to start inflammation, the consequent overproduction of the ACE2 receptor, and an important underlying cause of the most severe cases of COVID19.

Evaluation of the Efficacy of Omega-3 Fatty Acids Formulations in the Lipopolysaccharide-Induced Acute Lung Inflammation Rat Model

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. The O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour later, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3 groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress like COVID-19.

A study on the prevalence of gastrointestinal parasites in carnivores and its potential implications on human health

Zoonoses contribute an estimated 75% of new or re-emerging infectious diseases in humans with Covid-19 being the latest addition. Carnivores act as definitive hosts and reservoirs for several endoparasites with varied effects on human health. These interactions are fluctuating and adaptive, changing in response to various biotic and abiotic conditions. With the development of ‘One health movement’ more focus has been laid on zoonotic infections and their management. The present study showed that carnivores of Dampa Tiger Reserve (DTR) are host to several infectious parasites with a prevalence rate of 90.47%. Families like Felidae, Canidae, and Viverridae were found to host the maximum number of parasites. The parasite Paragonimus spp. were recorded to be present in the highest number (33 nos.) of scat samples followed by <i>Strongyle spp</i>. (27 nos.), <i>Ascaris lumbricoides</i> (23 nos.), and <i>Isospora spp</i>. (19 nos.). These parasites are known to infect humans through different modes like faecal-oral route, uncooked meat, fishes, and contaminated water and induced health implications like inflammatory in the brain, bronchitis, covert toxocariasis, acute lung inflammation etc. As the surrounding landscape of DTR continuous to shrink and humans are more prone to these parasites through their daily activities and lifestyle, the study will be crucial for providing a platform for future epidemiological study and diseases management in the region.

A peptide derived from chaperonin 60.1, IRL201104, inhibits LPS-induced acute lung inflammation

Chaperonin 60.1 (Cpn60.1) is a protein derived from M. tuberculosis that has been shown, along with its peptide fragment IRL201104, to have beneficial effects in models of allergic inflammation. To further investigate the anti-inflammatory properties of Cpn60.1 and IRL201104, we have investigated these molecules in a model of non-allergic lung inflammation. Mice were treated with Cpn60.1 (0.5-5000ng/kg) or IRL201104 (0.00025-2.5ng/kg), immediately before intranasal instillation of bacterial lipopolysaccharide (LPS). Cytokine levels and cell numbers in mouse bronchoalveolar lavage (BAL) fluid were measured 4h after LPS administration. In some experiments mice were depleted of lung-resident phagocytes. Cells from BAL fluid were analysed for inflammasome function. Human umbilical vein endothelial cells (HUVEC) were analysed for adhesion molecule expression. Human neutrophils were analysed for integrin expression, chemotaxis and cell polarisation. Cpn60.1 and IRL201104 significantly inhibited neutrophil migration into the airways, independently of route of administration. This effect of the peptide was absent in TLR4 and Annexin A1 knock-out mice. Intravital microscopy revealed that IRL201104 reduced leukocyte adhesion and migration into inflamed tissues. However, IRL201104 did not significantly affect adhesion molecule expression in HUVEC or integrin expression, chemotaxis or polarisation of human neutrophils at the studied concentrations. In phagocyte-depleted animals, the anti-inflammatory effect of IRL201104 was not significant. IRL201104 significantly reduced IL-1β and NLRP3 expression and increased A20 expression in BAL cells. This study shows that Cpn60.1 and IRL201104 potently inhibit LPS-induced neutrophil infiltration in mouse lungs by a mechanism dependent on tissue-resident phagocytes and to a much lesser extent the pro-resolving factor Annexin A1.

Contribution of Dipeptidyl peptidase 4 to Nontypeable H. influenzae-induced lung inflammation in COPD

Dipeptidyl peptidase 4 (DPP4) expression is increased in the lungs of chronic obstructive pulmonary disease (COPD). DPP4 is known to be associated with inflammation in various organs, including LPS-induced acute lung inflammation. Since non-typeable H. influenzae (NTHi) causes acute exacerbations in COPD patients, we examined the contribution of DPP4 in NTHi-induced lung inflammation in COPD. Pulmonary macrophages isolated from COPD patients showed higher expression of DPP4 than the macrophages isolated from normal subjects. In response to NTHi infection, COPD, but not normal macrophages show a further increase in the expression DPP4. COPD macrophages also showed higher expression of IL-1β, and CCL3 responses to NTHi than normal, and treatment with DPP4 inhibitor, diprotin A attenuated this response. To examine the contribution of DPP4 in NTHi-induced lung inflammation, COPD mice were infected with NTHi, treated with diprotin A or PBS intraperitoneally, and examined for DPP4 expression, lung inflammation and cytokine expression. Mice with COPD phenotype showed increased expression of DPP4, which increased further following NTHi infection. DPP4 expression was primarily observed in the infiltrated inflammatory cells. NTHi-infected COPD mice also showed sustained neutrophilic lung inflammation and expression of CCL3, and this was inhibited by DPP4 inhibitor. These observations indicate that enhanced expression of DPP4 in pulmonary macrophages may contribute to sustained lung inflammation in COPD following NTHi infection. Therefore, inhibition of DPP4 may reduce the severity of NTHi-induced lung inflammation in COPD.