Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications

Abstract

The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.

Tackling the COVID-19 “cytokine storm” with microRNA mimics directly targeting the 3’UTR of pro-inflammatory mRNAs

“…In fact, several studies found a clear relationship between the hyper-inflammatory state and the severity of the disease [6] , [7] , [8] , [9] . The pharmacological approach for treating ARDS needs of novel anti-inflammatory reagents as different COVID-19 patients might respond differently to these treatments [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] .…”

SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction

“…These results suggest that even if the endothelial layer is not infected the cell integrity gets disturbed, most likely by cytokines released by macrophages. In this respect, it is known that high cytokine/interferon levels can induce the disruption of the alveolar barrier function (Broggi et al, 2020;Gustafson et al, 2020;Pelaia et al, 2020).…”

Endothelial Cells and SARS-CoV-2: An Intimate Relationship

“…When the immune system generates an effective adaptive response against SARS-CoV-2, the infection can be eliminated and clinical manifestations are absent or may completely disappear [39]. A successful antiviral response is dependent on the expression of type I interferons (IFNs) [40][41][42] and on the activation of T lymphocytes (TCD4 + helper cells (Th) and TCD8 + cytotoxic cells), as well as specific antibody-producing B lymphocytes.…”

“…If the host organism does not develop an adequate adaptive immune response, the prolongation and amplification of innate mechanisms, combined with dysfunctional adaptive responses, lead to a hyperinflammatory state. The resulting intense and continuous release of proinflammatory cytokines underlies the cytokine storm [39] that is characteristic of acute respiratory distress syndrome (ARDS) [39][40][41][42], and is responsible for lung damage [39]. Patients with severe COVID-19 have decreased IFN production, as well as aberrant polarization of Th cells (predominantly Th17), increased expression of exhaustion-related surface markers, such as TIM3 and PD-1, and changes in the pattern of cytokine secretion [39,42,43] (Figure 1).…”

“…Epithelial/endothelial lesions mediated by cytokines/chemokines can impair the integrity of the blood/air barrier, promoting vascular permeability, alveolar edema, leukocyte infiltration (macrophages and neutrophils) and hypoxia [39]. IL-1β, generated by resident macrophages in response to activation of the NLRP3 pattern recognition receptor, plays a role in the recruitment and activation of neutrophils and is a key inducer of neutrophil extracellular traps (NETs).…”