IL-1 induces a significant number of metabolic and hematological changes. In experimental animals,
IL-1 treatments cause
hypotension due to rapid reduction of systemic blood pressure, reduced vascular resistance, increased heart rate and leukocyte aggregations.
IL-1 causes endothelial dysfunction, the triggering factor of which may be of a different nature including pathogen
infection. This dysfunction, which includes macrophage intervention and increased
protein permeability, can be mediated by several factors including
cytokines and
arachidonic acid products. These effects are caused by the induction of
IL-1 in various pathologies, including those caused by pathogenic
viral infections, including SARS-CoV-2 which provokes
COVID-19. Activation of macrophages by coronavirus-19 leads to the release of pro-inflammatory
cytokines,
metalloproteinases and other
proteolytic enzymes that can cause thrombi formation and severe respiratory dysfunction. Patients with
COVID-19, seriously ill and hospitalized in
intensive care, present systemic
inflammation, intravascular coagulopathy with high risk of thrombotic complications, and
venous thromboembolism, effects mostly mediated by
IL-1. In these patients the lungs are the most critical target organ as it can present an increase in the degradation products of
fibrin,
fibrinogen and
D-dimer, with organ lesions and
respiratory failure. It is well known that
IL-1 induces itself and another very important pro-inflammatory
cytokine, TNF, which also participates in hemodynamic states, including
shock syndrome in
COVID-19. Both
IL-1 and TNF cause
pulmonary edema,
thrombosis and
bleeding. In addition to
hypotension and resistance of systemic blood pressure,
IL-1 causes
leukopenia and
thrombocytopenia. The formation of thrombi is the main complication of the circulatory system and functionality of the organ, and represents an important cause of morbidity and mortality.
IL-1 causes platelet vascular thrombogenicity also on non-endothelial cells by stimulating the formation of
thromboxane A2 which is released into the inflamed environment.
IL-1 is the most important immune molecule in inducing
fever, since it is involved in the metabolism of
arachidonic acid which increases from vascular endothelial organs of the hypothalamus. The pathogenesis of
thrombosis, vascular
inflammation and angigenesis involves the mediation of the activation of the
prostanoid thromboxane A2 receptor. In 1986, in an interesting article (Conti P, Reale M, Fiore S, Cancelli A, Angeletti PU, Dinarello CA. In vitro enhanced
thromboxane B2 release by polymorphonuclear leukocytes and macrophages
after treatment with human recombinant
interleukin 1.
Prostaglandins. 1986 Jul;32(1):111-5), we reported for the first time that
IL-1 induces
thromboxane B2 (TxB2) releases in activated neutrophils and macrophages. An increase in
thromboxane can induce leukocyte aggregation and systemic
inflammation, which would account for the dramatic thrombi formation and organ dysfunction. Hence,
IL-1 stimulates endothelial cell-leukocyte adhesion, and TxB2 production. All these events are supported by the large increase in neutrophils that adhere to the lung and the decrease in lymphocytes. Therefore, ecosanoids such as TxA2 (detected as TxB2) have a powerful action on vascular
inflammation and platelet aggregation, mediating the formation of thrombi. The thrombogenesis that occurs in
COVID-19 includes platelet and cell aggregation with clotting abnormalities, and anti-clotting inhibitor agents are used in the prevention and
therapy of thrombotic diseases. Prevention of or induction of TxA2 avoids thrombi formation induced by
IL-1. However, in some serious vascular events where TxA2 increases significantly, it is difficult to inhibit, therefore, it would be much better to prevent its induction and generation by blocking its inductors including
IL-1. The inhibition or lack of formation of
IL-1 avoids all the above pathological events which can lead to death of the patient. The treatment of innate immune cells producing
IL-1 with
IL-1 receptor antagonist (IL-1Ra) can avoid hemodynamic changes,
septic shock and organ
inflammation by carrying out a new therapeutic efficacy on
COVID-19 induced by SARS-CoV-2.