The main clinical feature of severe COVID-19 is the appearance of acute respiratory distress syndrome [6]. Wang et al. [5] performed biopsy of lung tissue from patients with COVID-19 and found that the pathological features of COVID-19 are extremely similar to those of SARS and MERS, which are characterised by the desquamation of lung cells and the formation of transparent membranes. Liu Liang et al. [12] performed an autopsy of a patient with COVID-19 and found that the lungs of the deceased showed obvious inflammatory damage and exudative changes, a large number of sticky secretions overflowed from the alveolar section and fibrous cords were formed in the lung tissue. These studies suggested that inflammatory response is closely related to the progression of COVID-19. The purpose of this study was to investigate the correlation between the factors that mediate inflammatory response, such as cMPs and cytokines (IL-6, IL-8 and IL-10) and the severity of COVID-19 and determine whether the amount of cMPs and the expression of cytokines (IL-6, IL-8 and IL-10) can be used as indicators of the severity of COVID-19.
Inflammation is a protective immune response that helps clear the source of infection. However, excessive inflammation can cause immune damage as well. cMPs are vesicles produced by the remodelling and budding of cell membranes and are mainly composed of phospholipids and proteins. However, their internal components are not completely clear. cMPs are divided into platelet microparticles (PMPs), granulocyte MPs, erythrocyte microparticles (endothelial cell microparticles, EMPs) and lymphocyte-derived MPs according to their source [13]. Zafrani et al. found that cMP production was remarkably reduced in calpain knock-out transgenic mice, and the risk of inflammation, diffuse intravascular coagulation (DIC) and organ damage was greatly reduced. However, they found that the latter caused coagulation disorders and increased mortality when they injected cMPs from wild type mice with septicaemia into calpain knock-out transgenic mice [14], indicating that MPs are directly involved in calpain-mediated inflammatory injury during the course of sepsis. PMPs can stimulate the production of inflammatory factors, such as IL-1, IL-6, IL-8 and TNF-α. These cytokines, in turn, further activate inflammation and allowing cells to produce more cMPs, which exacerbate inflammatory response [15]. EMPs increase CD105 expression and decrease CD31 expression in the early stage of DIC and are directly related to the occurrence of DIC [16]. NMPs, especially those carrying high concentrations of IL-1β, are an important cause of tissue damage in several diseases [17]. This previous research shows that cMPs are closely related to the occurrence and development of inflammation and infection. In the present study, we isolated and detected cMPs in the blood of patients with COVID-19 of different levels of severity and of healthy persons. We found that cMPs in the blood of patients with COVID-19 were remarkably increased compared with those in healthy persons, and the number of MPs increased with the severity of COVID-19; thus, a remarkably positive correlation exists between them. The increase in cMP production is involved in the progression of COVID-19, and the number of cMPs may reflect the severity of COVID-19.
Recent studies have shown that MPs contain cellular receptors, cytoplasmic proteins, nucleic acids (RNA, microRNA and DNA) and cytokines. Among them, cytokines may be the key factor for mediating lung inflammation storms [18]. Alveolar macrophages in patients with severe pneumonia are stimulated to release a large amount of IL-6 and TNF-α in the early stages of infection [19]. The elevation of IL-6 levels can limit inflammation and protect the body to a certain extent at the early stage of disease. However, the excessive release of IL-6 can induce fibrinogen activation, activate coagulation factors, promote microthrombosis in inflammation sites and inhibit endothelial repair, which can make blood vessels highly permeable and further aggravate inflammatory lung injury [20]. IL-8 is the strongest neutrophil chemotactic and activating factor and has dual immune effects on the body. Low levels of IL-8 can protect against infection, and excessive IL-8 can induce inflammatory response. Higher IL-8 levels indicate a poor prognosis [21]. IL-10 is an anti-inflammatory factor that can down-regulate the host's immune response through T helper cells and inhibit the overexpression of pro-inflammatory cytokines. However, excessive anti-inflammatory response can inhibit the body's immune function, which is not conducive to the elimination of exogenous bacteria and viruses and results in a poor prognosis for patients [22]. We found that the expression of serum IL-6, IL-8 and IL-10 in patients with COVID-19 were higher than those in the control group and increased with the worsening of the disease. This result indicated that IL-6, IL-8 and IL-10 are involved in the inflammatory response process of COVID-19 and have important clinical significance for predicting the prognosis of patients. We speculated that IL-6 and IL-8 may play a role in promoting inflammation damage and IL-10 may play a role in suppressing the body's immune defence. In addition, we also found that older patients and patients with history of coronary heart disease accounted for a higher proportion in the severe and critically ill groups, further suggesting that the elderly and those with cardiac insufficiency and decreased immune function are more susceptible to the ‘inflammation attack’.
Alveoli are the main site of gas exchange in the lungs and the functional units of the lungs and are composed of types I and II alveolar cells, as well as alveolar macrophages and surfactants. We speculated that a large number of SARS-CoV-2 may induce cMP production to increase through multiple mechanisms (hypoxia, oxidative stress, cell activation, calcium influx, apoptosis, etc.) when these viruses invade type I and type II alveolar cells. Hence, alveolar cells and/or immune cells are activated to secrete TNF, IL-6, IL-8, IL-10 and other cytokines. Thus, the body's immune defence and anti-inflammatory balance are broken, and thus damage caused by pneumonia worsens. These cytokines further recruit inflammatory cells to the infection site and destroy type II alveolar cells, eventually leading to respiratory failure. We believe that increased cMP production may be the cause or result of the exacerbation of COVID-19.