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 Table of Contents  
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 39-41

COVID 19-lung interactions: the salient points for pulmonologist

1 Woodlands Multispeciality Hospital, Kolkata, West Bengal, India
2 Department of Anatomy, College of Medicine & Sagore Datta Hospital, Kamarhati, Kolkata, West Bengal, India

Date of Submission26-Jun-2020
Date of Acceptance30-Jun-2020
Date of Web Publication10-Sep-2020

Correspondence Address:
Dr. Arup Halder
MD (TB & Respiratory Diseases), Consultant Pulmonologist, 1/16/2, Manick Tala Main Road, Kolkata 700054, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jacp.jacp_40_20

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The COVID 19 virus gains entry into body by docking to ACE2 receptors of lungs. Subsequently it deranges the balance in RAS and destabilizes oxidant-antioxidant systems. It leads to cytokine storm and endothelial dysfunction. Intially lung is compliant but patients may be hypoxic due to vasoplegia. Later typical full blown ARDS set in.

Keywords: ACE2 receptors, Angiotensin 1-7, COVID-19, endothelial dysfunction, vasoplegia

How to cite this article:
Halder A, Halder A. COVID 19-lung interactions: the salient points for pulmonologist. J Assoc Chest Physicians 2020;8:39-41

How to cite this URL:
Halder A, Halder A. COVID 19-lung interactions: the salient points for pulmonologist. J Assoc Chest Physicians [serial online] 2020 [cited 2022 Dec 4];8:39-41. Available from: https://www.jacpjournal.org/text.asp?2020/8/2/39/294590

The COVID 19 pandemic is once a lifetime experience, hopefully. This pandemic has a tremendous impact on every aspect of life. The social, economical and healthcare-related changes are obvious and will affect everyone. In medical profession, many will be exposed to the disease. Few disciplines are more vulnerable than others, and include the Pulmonologist, as well. Being a ‘novel’ disease our knowledge is limited. We hardly know anything about the disease. But a good amount of observational studies is enriching our knowledge every day. There are few intricate things which are important for us. The present article will discuss the salient points on pathogenesis and pathophysiology important to a pulmonologist.


Previous studies showed SARS-CoV and NL63 Coronavirus employ ACE2 receptors for cell entry. We know that SAR-CoV caused an epidemic on 2002 and NL63 Coronavirus is an endemic strain. Based on the sequence similarities between Receptor Binding Motif (RBM) between SARS-CoV and COVID 19, several independent research groups investigated and found that the present virus uses the similar entry point.[1]

The COVID 19 virus enters the body through the respiratory route. It attaches to ACE2 receptors in the respiratory epithelium. ACE2 receptors are present in bronchial epithelial tissue including the trachea, bronchioles, and alveolar epithelium and capillary endothelium. Lung macrophages also contain ACE2 receptors.[2] After the initial engagement of COVID 19 Spike protein with ACE2 receptor, there is subsequent down regulation of ACE2 abundance on cell surfaces. Continued viral infection and replication contribute to reduced membrane ACE2 expression.

ACE2 actually acts on Angiotensin I and coverts it to Angiotensin 1-7, which is anti-inflammatory and vasodilator. So ACE2 counters the activity of Angiotensin Converting Enzyme (ACE) by reducing the amount of Angiotensin II and increasing the activity of Angiotensin 1-7, acting as negative regulator of Renin Angiotensin System (RAS). Down regulation of ACE2 receptors lead to increased activity of the vasoconstrictor and proliferative axis (Angiotensin II/ACE) and down regulation of protective axis (ACE2/Angiotensin 1-17). This in turn is associated with higher risks of acute thrombosis, destabilization of atherosclerotic plaques, enhanced platelet activity and coagulation.

On the other hand, Angiotensin Converting Enzyme Receptors (ACE receptor) are localized to blood vessels, both bronchial and parenchymal tissue. But smaller peripheral vessels had more ACE than larger sized vessels. Metzger et al demonstrated in 2011, a strong positive staining of ACE in human lung capillaries and less staining in larger pulmonary arterioles. The initial lung insults are more in the peripheral region than the central region in COVID19, as evidenced in CT thorax. Whether more upregulation of ACE receptors in lung peripheral vessels in COVID 19 is responsible or not is not known yet.

Interestingly, ACE2 is not only expressed on cell membrane, it is also expressed in nucleus.[3],[4] So it is hypothesized that nuclear ACE2, via an unknown mechanism, affects gene transcription, editing and repair, thus modulating cell proliferation, differentiation, and impact the healing process.

One interesting fact is though many of these Coronavirus use similar gateway, they differ considerably in clinical manifestations and virulence. It may be related to interaction of the virus and receptors. SARS-COV has a stronger receptor interference and higher ACE2 shedding leading to greater ACE2 down regulation, than NL63 Coronavirus. COVID 19 may have a receptor interference in between SARS-CoV and NL63 Coronavirus as the virulence is in between SARS-COV and NL 63 Coronavirus.

  Pathogenesis Top

The pathogenesis of any disease is important to predict symptoms and treatment. A ‘Novel’ virus like COVID 19 comes with much uncertainty as our understanding of pathogenesis is incomplete. The Spike (S) protein of virus binds to human ACE2 receptors. The entry into cells is accomplished by direct membrane fusion of the virus and plasma membrane. The RNA viral genome is released into the cytoplasm and is translated into 2 poly-proteins and structural proteins, after which the virus begins to replicate. At last, the virus particles fuse with plasma membrane and released outside to infect new cells.

Little is known about the antigen presentation process of COVID 19 infected cells, though this antigen presentation subsequently stimulates the humoral and cell mediated immunity. Recent studies of cellular immunity in COVID 19 infection have shown significant reduction of CD4 and CD8+ T cells from peripheral blood, which is difficult to explain. The T Cells once activated produce various cytokines via Th17 by a positive feedback loop. NF Kappa Beta pathway is activated by Interferon Regulatory Factor (IFR) and Toll like receptor 3, which produces large amount of Type 1 IFN. So the main cause of ARDS is cytokine storm, the deadly uncontrolled systemic inflammatory response from large amount of release of pro-inflammatory cytokines (IFN, IL 1, 6,12, 18, 33, TNF) and chemokines.[5],[6],[7]

The recent studies have shown the pathogenesis of the virus mainly depends on the actions on four systems- Renin Angiotensin System (RAS), Oxidative stress, Cytokine storm, and Endothelial dysfunction. Both the viral infection and RAS activation produces Reactive Oxygen Species (ROS) leading to oxidative burst. After the viral entry macrophages are activated by Toll like receptors, there is secretion of TNF Alpha, which in turn activates NADPH Oxidase. NADPH Oxidase is the main enzyme which stimulates production of ROS. The ROS now targets the virus. But NADPH is being overused by inflammation also brings in certain undesired changes in anti-inflammatory system.[8] The imbalance in RAS and excessive Angiotensin II leads to imbalance between two systems of Nitric Oxide synthesis. It decreases the endothelial NO Synthase (eNOS), which is anti-inflammatory, but increases the inducible NO Synthase (iNOS) which is pro-inflammatory and produce NO radicals. This imbalance between anti-oxidant and pro oxidant systems result in destruction of endothelial cells and give rise to a pro thrombotic state. Thus there are blockage of small vessels in lungs and formation of a hypoxic environment . In the hypoxic situation, there are more ROS generation and Hypoxia Inducible Factor 1 (HIF1) activation. Consequently it induces expression of Furic enzymes and further viral activation.[8]

  Pathophysiology Top

Gattinoni et al., based on their observations actually divided and phenotyped two groups of COVID 19 induced pneumonia and ARDS patients: the L type (or low type) and the H type (or high type). The type L is characterized by- low lung elastance (that means high compliance), low ventilation to perfusion ratio (meaning the hypoxemia is mainly due to loss of regulation of perfusion and loss of hypoxic vasoconstriction), low lung weight (meaning not much increase of water component in lung), and low recruitability (as the amount of non- areated tissue in lung is low, so the recruitability is low). The exactly opposite things occur in H or high type. They also nicely explained the probable mechanism of shift from L type to H type in an individual patient. The initial lung insult is a result of vasoplegia without any compromise of lung compliance. Vasoplegia means reduced systemic vascular resistance (and thus Blood pressure) in presence of normal or raised cardiac output. This is most commonly seen in septic shock.[9]

The driver of this vasoplegia may be Nitric oxide, Prostanoids, endothelin 1, reactive oxygen species. Reactive oxygen species is a strong stimulator of inducible Nitric Oxide Synthase 2 (NOS 2) which in turn produces NO. The potent dilator action of NO results in loss of pulmonary hypoxic vasoconstriction (thus increasing V/Q mismatch.[10] This hypoxic pulmonary vasoconstriction is thought to be a protective mechanism to reduce ventilation- perfusion (V/Q) mismatch. So any loss of this protective phenomenon will lead to hypoxia.

The normal response to this hypoxia will be to increase the minute ventilation with increased respiratory drive and resulting in increased respiratory rate and tidal volume. Tidal volume may rose up to 15 to 20 ml/ kg of ideal body weight. The increased respiratory drive results in increased input to diaphragmatic muscles and other muscles of inspiration with development of increased negative intrathoracic pressure. This increased negative intrathoracic pressure coupled with increased permeability of alveoli due to inflammation, as the disease progresses, will lead to alveolar edema. Patient may not complain about shortness of breath as long as lung compliance remains normal (as patient can inhale the volume he wants), but with development of edema the compliance decreases and patient starts to fill shortness of breath. As these changes progress further the compliance further falls, V/Q worsening occurs, lung weight increases and it becomes more recruitable due to loss of alveolar air. So this is how the L type changes to H type.[11] The airway involvement is not a problem in this disease. The respiratory failure is typically Type 1 or hypoxemic respiratory failure.

  Conclusion Top

The virus gains entry into the body through the respiratory route. The lungs are the initial destination of the virus where it proliferates. The ACE2 receptors are used for docking to human cells. The down regulation of ACE2 receptors tilts the balance of RAS and ultimately the oxidant-anti oxidant system. The hypoxia initially starts due to vasoplegia and takes the form of full blown ARDS as the disease progress in severity. But still there are many gaps in the knowledge. The proper understanding of pathogenesis and patho-physiology will help in adequate management of the disease.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Zhou P, Yang X, Wang X et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. https://doi.org/10.1038/s41586-020-2012-7  Back to cited text no. 1
Rajaram JI. The renin-angiotensin system enzymes in chronic obstructive pulmonary disease. University of Southampton, Faculty of Medicine, Doctoral Thesis, 2016, 163 pp. https://eprints.soton.ac.uk/397328/  Back to cited text no. 2
Gwathmey TM, Alzayadneh EM, Pendergrass KD, Chappell MC. Novel roles of nuclear angiotensin receptors and signaling mechanisms. Am J Physiol Regul Integr Comp Physiol 2012;302:R518-R530.  Back to cited text no. 3
Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001;37:1047-52  Back to cited text no. 4
Wang H, Yang P, Liu K et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008;18:290e301, https://doi.org/10.1038/cr.2008.15.  Back to cited text no. 5
Xu Z, Shi L, Wang Y et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Resp Med 2020 https://doi.org/10.1016/S2213-2600(20)30076-X.  Back to cited text no. 6
Cameron MJ, Bermejo-Martin JF, Danesh A et al. Human immunopatho-genesis of severe acute respiratory syndrome (SARS). Virus Res 2008;133:13e19, https://doi.org/10.1016/j.virusres.2007.02.014)  Back to cited text no. 7
Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Archives of Medical Research 2020 ISSN 0188-4409, https://doi.org/10.1016/j.arcmed.2020.04.019.  Back to cited text no. 8
Lambden S, Creagh-Brown BC, Hunt J et al. Definitions and pathophysiology of vasoplegic shock. Crit Care 2018;22:174. https://doi.org/10.1186/s13054-018-2102-1  Back to cited text no. 9
Jahn N, Lamberts RR, Busch CJ et al. Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice. Respir Res 2015;16:119. https://doi.org/10.1186/s12931-015-0274-7  Back to cited text no. 10
Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, Camporota L. COVID-19 pneumonia: different respiratory treatment for different phenotypes? Intensive Care Medicine 2020 doi: 10.1007/s00134-020-06033-2  Back to cited text no. 11


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