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 Table of Contents  
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 35

Pulmonary Covid fibrosis a new pharmaceutic approach

1 Biochemistry, Senior Scientist, University Milan Consultant, Italy
2 Researcher UOC, Infectious and Tropical Diseases, Spaziani Hospital Frosinone, Italy
3 Pharmacological Researcher, ASST Frosinone, Italy
4 Radiodiagnostic Department, Pisa University, Italy
5 Policliclinico San Donato Radiodiagnostic Department, Milan University, Italy

Date of Submission07-Aug-2020
Date of Acceptance21-Dec-2020
Date of Web Publication29-Mar-2021

Correspondence Address:
Roberto Menicagli
Biochemistry, Senior Scientist, University Milan Consultant, Mediglia - 20060
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpvm.IJPVM_462_20

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Background: Patient's post-COVID may develop chronic irreversible respiratory failure with “widespread signs of pulmonary fibrosis.” Our study analyzed the causes of this fibrosis to propose a therapeutic protocol. Methods: Identification of the biochemical causes of fibrosis in COVID-19 analysing the literature and chest CT. Results: The CT imaging shows pulmonary fibrosis. The viral infection produces “interleukin-6”, which binds to its receptor, in MUC1 of lung epithelial cells. The biochemical response of the cells promotes an over-expression of MUC1 with fibrosis. Interleukin6 also causes a metabolic imbalance in NO that promotes clots and atherosclerosis of the pulmonary vessels. These results show to promote NO endothelia's formation to block both the excessive expression of MUC1 and the atherosclerosis effect of the vessels. Conclusions: This study proposes to inhibit phosphodiesterase by vasodilatation of the pulmonary vascular bed and the MUC1 over expression by interleukin6, the Sildenafil with the SGLT2 and N-Acetylcysteine.

Keywords: COVID 19, fibrosis, lung

How to cite this article:
Menicagli R, Limodio M, Limodio M, Casotti MT, Menicagli L. Pulmonary Covid fibrosis a new pharmaceutic approach. Int J Prev Med 2021;12:35

How to cite this URL:
Menicagli R, Limodio M, Limodio M, Casotti MT, Menicagli L. Pulmonary Covid fibrosis a new pharmaceutic approach. Int J Prev Med [serial online] 2021 [cited 2022 Aug 15];12:35. Available from: https://www.ijpvmjournal.net/text.asp?2021/12/1/35/312525

  Introduction Top

”Patients discharged after contracting Covid-19 may become chronically ill due to respiratory complications”.[1] Many, about a 30% of them, return to the hospital and present embolism, phlebitis, vacuities, and lung relics. It is very likely to have a cohort of patients with fibrotic remnants in the lungs. These fibrotic patients show large scars on the lung with irreversible respiratory impairment, which creates respiratory problems even after a simple walk”. This also occurs in young patients, with an incidence ranging from 30 to 75 percent of the assessed cases. We think that pulmonary fibrosis may be the danger post COVID, needs for specific clinical screening dedicated to the follow-up of patients post COVID especially who had cures for lung complications especially the most severe and the frailest.[2] These will need active pharmacological treatment 1nd dedicated rehabilitation pathways.[3] We also expect to do chest X-rays, respiratory function tests, 6-minute walking tests, chest and cardiac ultrasound and chest CT to investigate if a diffuse interstitial neuropathy or pulmonary embolism is present. Our study aims find with the analysis of the literature and the radio diagnostic imaging of the fibrosis in COVID, its most plausible biochemical causes to propose the most right therapeutic protocol.

  Results Top

Many patients discharged from COVID-19 return to the hospital with signs of respiratory failure have a typical CT scan image of pulmonary fibrosis, [see [Figure 1]]. The CT scan on the first day of admission revealed tissue or fluid blocking blood vessels in both lungs, although at this stage it was mainly limited to the right lower lobe. The CT images fade to the fifteenth day, but the blurred patches in the lower left lung indicate tissue filled with fluid and not air, which can cause further damage. It is important to check the biochemical mechanisms that trigger the fibrosis process. Viral infection produces various inflammatory compounds in excess, the most important of which is interleukin 6. Our study hypothesizes that interleukin-6 binds to cells that have its IL-6R receptor on the surface, triggering many pro-inflammatory actions, including: Production of the VEGF protein by fibroblasts, with the consequent response of endothelial blood vessel cells and increased permeability of the vessels themselves.[4] It is also possible to hypothesize that interleukin 6 induces to form a process of atherosclerosis of the vessels: Interleukin-6 (IL-6) in fact could influence the endothelial interaction of nitric oxidesynthase (eNOS) -caveolin-1[5] and decide a reduced bioavailability of nitric oxide in the context of inflammation, contributing both to the narrowing of the lumen and to the fibrosis of the same.[6] Many of the effects of IL-6 on vascular function and structure are representative of the loss or to cut the nitric oxide (NO) biodisponibilty. IL-6 has direct effects on the activity and expression of nitric oxide endothelial synthase as well as on the increase in vascular superoxide, which rapidly inactivates NO and thus limits bioavailability. The report of IL-6 involving its IL6R receptor, mediates a range of effects in the vascular wall, including endothelial activation, vascular permeability, immune cell recruitment, endothelial dysfunction, as well as vascular hypertrophy and fibrosis. Our study demonstrates an aberrant production of MUC1 during the inflammatory cascade that produces fibrosis.[6] The MUC1 protein has an N-terminal subunit (also called KL-6) consisting of a variable extracellular number of units (VNTR).[7] We hypothesize that interleukin 6 interacts with its receptor IL-6R present on the extracellular domain of MUC1, translating and amplifying the signal for a new synthesis of MUC1 The excess of interleukin 6 causes over-expression of MUC1 and formation of fibrosis.
Figure 1: TAC of lungs in 65-year-old women with COVID-19

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Our study show restores the balance to form the endothelial NO so to block both the over expression of MUC1 and the atherosclerotic effect of the vessels. We propose Sildenafil, a selective inhibitor of phosphodiesterase type 5 cGMP-specific (PDE5).[8] To inhibit the PDE5 causes vasodilatation of the pulmonary vascular bed: High levels of cGMP show a decrease in intracellular Ca2+ deposits with relaxing action on the endothelial cells. Sildenafil can be decisive both in the acute phase to prevent the formation of clots through the vasodilator and both for a antiaggregant effect in the chronic and fibrotic phase for the restoration in the biosynthesis of NO…[8],[9] In this literature review work we have reviewed how recent research has studied the effects of antidiabetic compounds on periarterial fibrosis In particular Empagliflozin belonging to the class of sodium-glucose carrier inhibitors type 2, SGLT2 which the physicians use in non-insulin-dependent type 2 improves periarterial and tubulointerstitial fibrosis in the kidney.[10] Empagliflozin suppresses advanced glycation end products (AGE), restores endothelial nitric oxide synthase (eNOS) activation and reduces interstitial and periarterial nitrous-oxidative stress.[10],[11] The fibrotic conditions involve over expression of MUCA5c; we acetylcysteine[12] that improves inflammations as well prevents mucin's production. Its use in post COVID-19 fibrosis is important; it is known that in diabetics where lung complications are commonly present this class of compounds SGLT2 stimulates surfactant production in alveolar type 2 cells as well as for mucin.[12]

  Conclusions Top

This study proposes to promote NO endothelia's formation to block both the excessive expression of MUC1 and the atherosclerosis effect of the vessels. This study proposes to inhibit phosphodiesterase by vasodilatation of the pulmonary vascular bed and MUC1 over-expression by interleukin6. the use of Sildenafil with SGLT2 and N-Acetylcysteine The protocol give sildenafil citrate 25 mg/die, acetyl cysteine 600 mg × 3/die empagliflozin 100 mg/die.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Zuo W, Zhao X, Chen Y G. SARS coronavirus and lung fibrosis. Mol Biol SARS Coronavirus 2009:247-58. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC7176214/ Molecular Biology of the SARS-Coronavirus. [Last accessed on 2009 Jul 22]. doi: 10.1007/978 3 642 03683 5_15.  Back to cited text no. 1
George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID 19: The potential role for antifibrotic therapy. Lancet Respir Med 2020;8:807-15.  Back to cited text no. 2
Isidori AM, Giannetta E, Pofi R, M.A. Venneri, D Gianfrilli, F. Campolo, CM Mastroianni, A. Lenzi, and G. d'Ettorre Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection Andrology. 2020: 10.1111/andr.12837.  Back to cited text no. 3
Didion SP. Cellular and oxidative mechanisms associated with interleukin 6 signaling in the vasculature. Int J Mol Sci 2017;18:2563.  Back to cited text no. 4
Hung M J. Interleukin 6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin 1 in human vascular endothelial cells. J Hypertens 2010;28:940-51.  Back to cited text no. 5
Ballester B, Milara J, Cortijo J. Mucins as a new frontier inpulmonary fibrosis. J Clin Med 2019;8:1447.  Back to cited text no. 6
Dal Moro F, Livi U. Any possible role of phosphodiesterase type 5 inhibitors in the treatment of severe COVID19 infections? A lesson from urology. Clin Immunol 2020;214:108414.  Back to cited text no. 7
Mondaini N. Phosphodiesterase type 5 inhibitors and COVID 19: Are they useful in disease managment? World J Mens Health 2020;38:254-5.  Back to cited text no. 8
Isidori AM, Giannetta E, Giannetta, Pofi R, Venneri MA, Gianfrilli D, Campolo F, et al. Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection Andrology. 2020:10.1111/ andr.12837.  Back to cited text no. 9
Chowdhury B, Luu AZ, Luu VZ, Kabir MG, Pan Y, Teoh H, et al. The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension. Biochem Biophys Res Commun 2020;524:50-6.  Back to cited text no. 10
Aroor AR, Das NA, Carpenter AJ, Habibi J, Jia G, Ramirez Perez FI, et al. Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistive index and kidney injury. Cardiovasc Diabetol 2018;17:108.  Back to cited text no. 11
Zhang Q, Ju Y, Ma Y, Wang T. N acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia. A randomized controlled trial. Medicine (Baltimore) 2018;97:e13087.  Back to cited text no. 12


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