The role of hyaluronan synthesis and degradation in the critical respiratory illness COVID-19.

Hyaluronan (HA) is a polysaccharide found in all tissues as an integral component of the extracellular matrix (ECM) that plays a central regulatory role in inflammation. In fact, HA matrices are increasingly considered as a barometer of inflammation. A number of proteins specifically recognize the HA structure and these interactions modify cell behavior and control the stability of the ECM. Moreover, inflamed airways are remarkably rich with HA and are associated with various inflammatory diseases including cystic fibrosis, influenza, sepsis, and more recently coronavirus disease 2019 (COVID-19). COVID-19 is a worldwide pandemic caused by a novel coronavirus called SARS-CoV-2, and infected individuals have a wide range of disease manifestations ranging from asymptomatic to severe illness. Critically ill COVID-19 patient cases are frequently complicated by development of acute respiratory distress syndrome (ARDS), which typically leads to poor outcomes with high mortality rate. In general, ARDS is characterized by poor oxygenation accompanied with severe lung inflammation, damage, and vascular leakage and has been suggested to be linked to an accumulation of HA within the airways. Here, we provide a succinct overview of known inflammatory mechanisms regulated by HA in general, and those both observed and postulated in critically ill patients with COVID-19.

INTRODUCTION

The devastating pandemic outbreak of the novel coronavirus disease (COVID-19) is unprecedented and continues to be a public health emergency worldwide (1). As of January 2022, more than 66.5 million cases and 850 thousand deaths are reported in the United States alone after 2 years of the first reported case from China, with no clear end in sight (2–4). The disease is caused by a single stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (5) belonging to the zoonotic coronavirus family and comprises four structural proteins known as spike (S), envelope (E), membrane (M), and nucleoprotein (N) (6). The novel SARS-CoV-2 shares 79.6% sequence identity to SARS-CoV-1, which caused a multicounty outbreak in 2002 to 2003, and ∼50% identity with MERS-CoV (Middle East respiratory syndrome), which caused an outbreak in Saudi Arabia in 2012 (7, 8).

COVID-19 can cause mild to severe respiratory illness after exposure to airborne infectious respiratory droplets (9, 10). Severe cases manifest with viral pneumonia and acute respiratory distress syndrome (ARDS), a sudden and potentially fatal form of respiratory failure (11). COVID-19 ARDS carries a high mortality rate characterized by poor oxygenation accompanied by severe lung inflammation and damage (12). Early investigations described the accumulation of clear, highly viscous fluid in lung autopsy specimens from deceased patients (13–15). These findings implicated the glycosaminoglycan (GAG) hyaluronan (HA) as a potential cause of fatalities in COVID-19 due to its ability to form a gel-like structure with high viscosity present in respiratory secretions in several inflammatory lung diseases, including influenza, which also is associated with ARDS in many critically ill patients (16–21). Since these initial observations early on in the pandemic, HA has emerged as a component of the dysregulated immune response associated with COVID-19.

HA is an integral component of the extracellular matrix (ECM) and plays several important roles in physiological and pathological processes (22–24). HA is one molecule of a group of polysaccharides known as glycosaminoglycans (GAGs), a family of unbranched single-chain polymers of disaccharide units. The HA polymer is composed of repeating disaccharides D-glucuronic acid and d-N-acetylglucosamine, linked by β (1, 4) and β (1, 3) glycosidic bonds (25), and unlike other GAGs, is not covalently attached to a peptide. It is retained at the cell surface as a linear polysaccharide through interactions with several binding proteins collectively termed “hyaladherens” which grant HA diverse biological activities (25, 26). HA plays crucial roles in ECM signaling, tissue healing, inflammation, angiogenesis, endothelial and epithelial barrier functions, bone remodeling, tumor progression, homeostasis, and cell proliferation and migration and becomes elevated in response to infection, inflammation, and tissue injury (22–24, 27, 28). The ubiquitous expression of HA leads to important roles in almost all areas of physiology and is just one component of a heterogeneous ECM that provides important cues to cells. Unlike other GAGs, which are synthesized in the Golgi, the majority of HA is synthesized by three membrane bound HA synthases (HAS1, HAS2, HAS3) enzymes. Each HA synthase has different biosynthetic characteristics and regulatory systems, but all synthesize HA at the surface of the plasma membrane where the nascent polysaccharide chain is extruded directly into the extracellular space and tethered to the cell surface by hyaladherins (29). The molecular weight distribution is predominantly regulated by a balance of synthesis by the HAS enzymes and catabolism by the hyaluronidases (HYALs) Hyal-1 and Hyal-2 (Fig. 1) (30) and can range from <50 kDa to ∼104 kDa. In recent years, HA degrading proteins structurally different from the HYAL family have been identified. The cell migration inducing protein (CEMIP), also known as KIAA1199, and the transmembrane protein 2 (Tmem2) both have been shown to contribute to extracellular degradation of HA in fibroblasts (31–34). Therefore, the regulation of HA synthesis and degradation regulates to the bioavailability of different HA forms with discrete biological properties. HA within the ECM and glycocalyx is continually turned over, resynthesized, and bound by HA binding proteins, which together regulate receptor engagement and signaling to drive cell-type-specific effects. High-molecular-weight HA (HMW-HA) is viewed as the physiologically available, anti-inflammatory, anti-angiogenic, repair promoting form important for homeostasis. HA provides cells with their own microenvironment, acting as a barrier that excludes other molecules by steric forces. The degree of exclusion increases on the size of HA, which results in greater concentration of plasma proteins, such as cytokines and antibodies. In addition to molecules, HMW-HA also can exclude immune cells and impede viral recognition of cell-surface receptors. These properties disappear on loss of HA by treatment with hyaluronidase, and this combination of loss of protective functions and novel roles of low-molecular-weight HA (LMW-HA) fragments supports the notion of degradation products as proinflammatory, proangiogenic, damage-associated molecule capable of triggering sterile inflammation by recognition through Toll-like receptors (TLRs) (35). Both HMW-HA and LMW-HA fragments signal through TLRs as well as hyaladherins, and both polymer size and cell-type-specific responses ultimately determine biological outcomes (36). In this review, we will provide a summary of known roles of HA in the lung during health and highlight known and possible roles of HA in the pathobiology of COVID-19.

Figure 1.

Model for synthesis and degradation of HA. Hyaluronan is synthesized by membrane-bound synthases (HAS) on the inner surface of the plasma membrane, and the chains are extruded through pore-like structures into the extracellular space. The HA synthases HAS 1–3 produce HA in the plasma membrane of different sizes and rates. The catabolism of HA and hence the molecular weight distribution is predominantly regulated by the hyaluronidase (HYALs) family, Hyal-1 and Hyal-2. In recent years, newly discovered HA degrading proteins were also identified. The cell migration inducing protein (CEMIP), also known as KIAA1199, mediates the intracellular degradation of HA whereas the transmembrane protein 2 (Tmem2) controls the extracellular degradation. HA and fragments may bind to many different hyaladherins in the extracellular matrix, on the cell surface and intracellularly such as CD44, RHAMM, TSG-6, and inter-α-inhibitor heavy chains. HA, hyaluronan.

HA Is Localized throughout the Airways Where It Contributes to Homeostasis

The respiratory system is made up of airways and lung parenchyma, with the trachea, bronchi, and bronchioles collectively referred to as airways. The parenchyma comprises a large number of thin-walled alveoli, the functional units where gas exchange with pulmonary vasculature takes place, a simple epithelial layer, alveolar septum, interstitial space, and capillary endothelium (37). The alveolar septum, the wall between adjacent alveoli, is lined by the alveolar epithelial type I (type I pneumocytes) and type II cells (type II pneumocytes) (38). The connective tissue core of the septum possesses connective tissue cells including fibroblasts. In addition, alveolar macrophages escort the area between the connective tissue and the lumens of the alveoli and serve as the first line of defense of the respiratory tract. HA is present in the region around bronchial and bronchiolar epithelium, alveolar space, alveolar septum, and also within the pulmonary endothelial glycocalyx (39, 40). In healthy lung tissue, HMW-HA is the predominant form where it modulates lung tissue homeostasis, promotes optimal cell survival conditions, and maintains a firm ECM structure (41, 42). As with other tissues, HA is produced by different HAS enzymes in a cell-type-specific fashion within the lung (43, 44). HAS2 generates very high molecular mass HAs and is expressed by type II alveolar epithelial cells and others (44), and HA is present at both the surface epithelium and the basal lamina. Accordingly, HMW-HA is present on the surface of the airway epithelium where it is believed to have barrier-enhancing properties (45, 46), acts to scaffold enzymes for mucosal defense such as kallikrein and lactoperoxidase (45), increases ciliary beat frequency (47), and can also be released from the cell surface into alveolar fluids. In other contexts, homeostatic HMW-HA has been shown to diminish production of inflammatory cytokines, negatively regulate TLR signaling, and promote production of anti-inflammatory cytokines including IL-2, IL-10, and TGF-β, and it is plausible these mechanisms exist in the lung as well (48, 49). Leukocyte-adhesive “HA rafts” have been found to be released into the extracellular space from the apical surface of murine airway epithelial cells (AEC) in vivo and from AEC lift cultures in vitro and are suggested to have a role as a host defense mechanism in retraining leukocytes at a crucial host-pathogen interface (50). Multiple studies support the observation of high levels of HA in bronchoalveolar lavage (BAL) fluid isolated from patients with lung disease such as influenza, sarcoidosis, cystic fibrosis and others in comparison to healthy subjects (17, 18, 51, 52). In the alveolar airway under healthy conditions, HA levels are believed to be kept low by turnover by alveolar macrophages (AM) which take-up and degrade HA in vitro (53). The alveolar HA interacts with specific cell-surface receptors, such as CD44, induces intracellular signal transduction, and creates a protective layer around the cells, by which it acts to dampen other possible interactions within the microenvironment (19). For example, the HMW-HA binds to CD44 expressing cells including the basolateral surface of bronchial epithelium and alveolar macrophages and the HMWHA-CD44 cell-coat prevents apoptosis by masking cell death receptors and acts as a regulator of prosurvival mechanisms (27).

These observations suggest HA from epithelial cells in the lung contributes to airway homeostasis in multiple levels. In the healthy lung, HA levels are low in the alveolar space and support alveolar macrophage survival, whereas HA in the basement membranes of bronchioles and perivascular areas provide support to surrounding cells. Thus, at the apical surface, HA regulates the availability of enzymes and immune cells important in host defense and basolaterally by organizing the ECM to control wound healing, tissue repair, and maintenance of epithelial integrity. Degradation of HA can promote loss of these protective qualities and generation of fragments implicated in disease progression.

Generation of Inflammation-Associated HA Fragments and Their Immunostimulatory Effects

During inflammation, HA levels dramatically increase in the lung and reach its peak with maximum leukocyte infiltration (54). The degradation of HMW-HA into smaller fragments starts by the activities of Hyal-2, TMEM2, CEMIP, and reactive oxygen species (ROS) at cell surfaces (16). The smaller LMW-HA fragments may then be bound and cleared by AMs with further intracellular degradation mediated by Hyal-1 (and possibly CEMIP) and by the activity of exoglycosidases (β-glucuronidase and β-N-acetylhexosaminidase) (31–34, 55). The LMW-HA fragments are bioactive polymers with a polydisperse molecular weight distribution in the range of ∼104–105 Da (56). A shift in HA size toward LMW-HA fragments occurs in response to damage and infection and initiates host-defense and repair mechanisms. However, if unresolved can lead to inflammatory consequences (57). Data generated from studies of human disease and animal models have shown elevated levels of LMW-HA in multiple lung pathologies as a consequence of the inflammatory response (17, 18, 20, 58–60). For example, tissue damage and inflammation leads to a dramatic accumulation of HA driven by increased HAS2 expression in lung pathologies including asthma and influenza (21, 61). However, HA breakdown also becomes increased by several specific hyaluronidase enzymes as well as reactive oxygen species (62). This process generates a wide distribution of HA fragments that can trigger a cascade of signaling events leading to an immense inflammatory response while also competing with HMW-HA to disrupt protective responses. The production of HA matrices during inflammation is well known to facilitate the influx of immune cells to the site of injury and is primarily orchestrated by HA-CD44 interactions (63, 64). CD44 is a type 1 transmembrane glycoprotein and considered the primary cell surface receptor for HA (65). It is widely expressed in neutrophils, macrophages, fibroblasts, epithelial, and endothelial cells (28, 66). In addition to facilitating immune cell recruitment to sites of inflammation, CD44-HA interactions also support signaling and cytokine release (67). For example, purified HA-fragments released by platelet Hyal-2 from the surface of endothelial cells have been shown to stimulate monocytes to produce IL-6 and IL-8 (68). HA fragments in other contexts are known to induce cytokines such as TNF-α, RANTES, MIP1β, MCP-1, IL-6, IL-8 and others from innate immune cells including monocytes, macrophages, and dendritic cells, and many of these effects are thought to be mediated by a combination of CD44 and TLRs and likely also occur in the lung (68–76). For example, LMW-HA also promotes inflammation by activating epithelial cells through induction of IL-8 and IP-10 (77). The role of HA signaling via TLRs in various immune cells such as T cells, monocytes, and dendritic cells as well as nonimmune cell-types also present within the lung including epithelial cells, endothelial cells, and fibroblasts has been well studied (69, 72–76, 78, 79). Although the prevailing view is that cross talk between these cells and HA fragments provokes a proinflammatory response and interaction between HMW-HA and TLRs maintains cell integrity by inhibiting inflammation (57, 78, 80), to date there is limited evidence that HA binds or interacts directly with TLRs, and it is possible that the size-dependent effects are due to different abilities of polymer lengths to cluster interacting receptors and engage different ECM binding partners. In addition to CD44 and TLRs, the receptor for HA-mediated motility (RHAMM) also plays an important role in recognition of HA downstream signaling during inflammation (57, 67). RHAMM is present in several cell types, including macrophages, and is capable of interacting with HA at cell surfaces. As its name suggests, binding of RHAMM to HA controls cell motility and chemotaxis of macrophages into inflamed tissues (81), while also triggering downstream signals necessary to control inflammation and tissue repair (82–85). However, studies have demonstrated CD44 and RHAMM can act in a complex induced by HA (67, 86), and some redundancy may exist between biological effects regulated by each receptor. For example, experiments performed by Nedvetzki et al. (87) determined that inflammatory mechanisms mediated by CD44-HA interactions such as leukocyte migration and transcriptional regulation are compensated for by RHAMM in CD44-deficient murine models of arthritis.

The induction of HA synthesis is clearly triggered by infection, inflammation, and pulmonary injury where it plays an important role in recruitment of immune cells. The production of HA fragments, which are the result of ECM remodeling, possess potent biological effects as endogenous “danger signals” that participate in the inflammatory process. Although HA is capable of engaging many receptors at the cell surface, how specific sized HA molecules control receptor engagement and the hierarchy of receptor interactions, which determine the direction of protective or inflammatory events, remains to be elucidated.

Heavy Chain-Modified HA (HC:HA): A Unique Tissue Protective Matrix

There is an intimate connection in many inflammatory disease states between elevated HA levels and its localization with infiltrating immune cells. Leukocytes are frequently observed embedded in HA matrices within perivascular and submucosal regions. The past two decades of research into the biological effects of HA have clearly demonstrated that several extracellular hyaladherins including inter-α-trypsin inhibitor (IαI) and tumor necrosis factor-stimulated gene 6 (TSG-6) become upregulated during lung inflammation and development and play an essential role in dictating the biological effects of HA (88). Inter-α-inhibitor is a proteoglycan, composed of two heavy chains (HCs) and one light chain, produced by the liver, and is found abundantly in serum. Lung epithelia, fibroblasts, and airway smooth muscle are among several cells that also express IαI (89). TSG-6 is a hyaladherin with enzymatic activities that catalyzes the covalent substitution of HA with IαI heavy chains to yield the HC:HA matrices (90, 91). Although TSG-6 is not constitutively expressed, it can be rapidly induced by TNF-α, interleukin (IL)-1, lipopolysaccharide (LPS), and prostaglandin E2 on inflammation (88, 92, 93). For example, elevated levels of TSG-6 have been observed in asthmatic BAL fluid, in the airway epithelium and secretions of smokers, and serum of inflammatory bowel disease patients (94, 95). In regards of HC-HA complexes, the TSG-6-mediated cross linking creates a highly dense, cable-like matrix that significantly increases the migration, adhesion, and persistence of immune cells into the cross-linked HA (90). The modification of HA with HCs containing von Willebrand factor A domains expands the biological functions of HA within the ECM. These HC-HA products have been detected in sera of patients with rheumatoid arthritis among other inflammatory diseases (96–98). Increased HC:HA matrices are observed in the lungs of patients with asthma when compared with control (99). Study of TSG-6 null mice in a model of asthma provides evidence that the absence of TSG-6 and HC:HA cross linking leads to a markedly milder form of asthma including less HA, reduced leukocyte infiltration, and lower airway hyperresponsiveness (100). In other contexts, secretion of TSG-6 by human adipose-tissue-derived mesenchymal stem cells was shown to reduce inflammation in murine models of colitis by induction of M2 macrophage polarization (101). These data are consistent with studies supporting the notion that TSG-6 modification of HA possesses tissue protective and anti-inflammatory effects by promoting clearance of apoptotic neutrophils by macrophages (102).

Ultimately, although HC:HA has well established immune-cell recruitment properties and is observed at high levels within inflamed tissues, the effect that this distinct form of HA has on immune cell phenotypes has only recently begun to emerge. It is overwhelmingly likely that in most animal models of inflammatory disease, many of the mechanistic roles attributed to HA in vivo are in fact mediated by HC:HA in tissue. Delineating how HC:HA matrices control respond to engagement and the biological effects of HA degradative enzymes on these matrices remains to be established.

HA Has Emerged as an Inflammatory Mediator of COVID-19

As the pandemic has progressed, so have investigations into the role of HA in lung and extrapulmonary manifestations of COVID-19. Early observations implicated HA as a potential cause of fatalities in COVID-19 due to the presence of a hyperviscous gel-like structure found in the lungs of deceased patients with COVID-19 who shared similarities to prior observations of patients with severe influenza ARDS (16–21). HA is known to play a role in numerous respiratory diseases including cystic fibrosis (CF), and unsurprisingly, HA was also found in respiratory secretions of patients with COVID-19 by multiple groups. The study by Kaber et al. (13) reported increased levels of HA in sputum samples from intubated patients with COVID-19. The study examined tracheal aspirations collected from eight COVID-19 intubated patients, six positive controls obtained from patients with CF, and eight negative controls obtained from healthy individuals. A substantial increase (∼ 20-fold) in sputum HA levels was detected in both, the COVID-19 and the CF samples, compared with healthy controls and indicated comparable levels of HA in patients with COVID-19 to those with CF. Analysis of HA indicated much of the polymer was present as LMW-HA within the lung, a phenotype that predominates at sites of active inflammation, suggesting degradation by HYALs in concert with ROS. Examination of histological sections of cadaver lung by both groups determined that HA is present in the alveolar spaces of COVID-19 lungs (13, 14). Hellman et al. observed the presence of alveolar HA in three patients with severe COVID-19, two of whom were treated in the intensive care with signs of hyperinflammatory syndrome, like those seen in ARDS (14). Similar findings in patients with ARDS due to other pathologies, including sepsis, have also been reported, suggesting increased alveolar deposition of HA is a common mechanism (103–105). For example, the study by Roger et al. reported increased levels of circulating and alveolar HA in a small set of 12 patients with ARDS (104). These findings were confirmed by Anthony et al. in a larger set of 86 patients with ARDS (103). The observed buildup of alveolar HA suggests its involvement in the accumulation of fluids in the lungs or edema, a characteristic of ARDS. In fact, Modig and Hällgren (104) demonstrated an increase of up to 82 times in alveolar HA concentration in ARDS compared with controls. These studies have demonstrated an association between increased alveolar and vascular HA levels with the severity of lung injury and systematic organ dysfunction, respectively (103), but it is unclear yet if HA is a contributing cause or effect of lung injury in ARDS. However, alveolar edema reduces gas exchange, which leads to hypoxemia, and in vitro, hypoxia stimulates the production of HA and upregulates hyaluronidase activity (106). And it is also likely that in the inflamed alveoli, HA can be further degraded by the reactive oxygen species (ROS) produced by the infiltrating neutrophils (40).

Consequently, in many settings including COVID-19, the levels of LMW-HA fragments are substantially elevated systemically. LMW-HA fragments have been reported to activate alveolar macrophages and induce the release of inflammatory mediators, including cytokines, chemokines, and growth factors by several cell types. Thus, HA can participate as one factor capable of enhancing the cytokine storm associated with COVID-19 and contribute to disruption of epithelial cell integrity causing increased permeability of the alveolar-capillary membrane (107). Endothelial cells make up almost one-third of lung tissue and act as a selective, protective cellular barrier regulating the interface between the circulating cells, blood, and the vessel wall (108). Disruption of the endothelial cell barrier is a critical feature of inflammation, as well as an important contributing factor to acute lung injury and ARDS because it results in leakage of fluid, protein, and cells into lung air spaces. Injury to the endothelium and coagulation are characteristics of many critical illnesses, and several studies have implicated glycocalyx shedding is present in COVID-19 (109–111). Examination of plasma GAG levels and GAG-degrading enzymes from healthy donors and hospitalized or ICU-admitted patients with COVID-19 indicate that HA and heparan sulfate and the enzymes responsible for their degradation circulate at significantly increased levels in COVID-19 when compared with controls, and at similar levels to those observed in patients with sepsis (112). Similar to HA observed in the lung of patients with COVID-19, HA in circulation is present as LMW fragments, which when cultured with endothelial cells is capable of promoting vascular barrier permeability in a CD44- and RhoA/Rho-associated protein kinase-dependent mechanism (112). These data suggest that breakdown of vascular barrier function due to HA degradation is a possible doorway by which HA from circulation or the alveoli could further amplify systemic inflammation. It is pertinent to note that to date, one-third of hospitalized patients with COVID-19 and three-quarters of ICU-admitted patients with COVID-19 develop ARDS (113, 114). Other respiratory pathogens such as respiratory syncytial virus (RSV) and influenza virus along with the viral mimetic, polyinosine-polycytidylic acid (poly I:C) have been reported to cause accumulation of HA (21, 115–117). Given the observations of increased HA in COVID-19, it is possible that recognition of SARS-CoV2 may also have a similar effect on HA production. Using a combination of samples from severely ill patients and a transgenic murine model of COVID-19, Donlan et al. (118) found an IL-13-dependent increase of HA levels in the lungs of infected mice driven by increased HAS1 expression. Importantly, blockade of IL-13 (which is associated with improved outcomes in patients) or CD44 resulted in improved clinical measures of disease and survival in mice. Further, intranasal administration of IL-13 in mice also led to increased HA deposition within the lung, suggesting that HA production and signaling are likely downstream of IL-13 and contribute to disease outcome in both mice and patients (118).

One possible mechanism by which SARS-CoV2 induces the formation of HA fragments is through a dysregulation of HA production and degradation resulting from overactivation of innate and adaptive immune responses and the resulting cytokine storm. During the course of infection, alveolar epithelial cells and macrophages release inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, IL-10, IL-18, and interferon-α) and chemokines (e.g., IP-10 and MCP1) (119, 120). IL-8 and other chemoattractants recruit a variety of leukocytes including neutrophils and T-helper cells to the site of infection. Meanwhile, HMW-HA levels are dramatically increased in response to HAS overexpression due to increased levels of cytokines such as IL-1β and TNF-α. In addition to activating HAS1 and HA deposition, IL-13 was also shown to promote HYAL2 expression in a murine model of COVID-19 (118). HA fragments present in circulation of patients with COVID-19 were demonstrated to promote endothelial barrier permeability in a CD44 and ROCK-dependent mechanism (112). As the inflammatory response goes on, the degranulated neutrophils release neutrophil extracellular traps (NETs), which are a hallmark of COVID-19 in the lung, along with reactive oxygen and nitrogen species. Together, a combination of HYAL activity and reactive species breaks down the accumulated HA into smaller molecular weight fragments. These proinflammatory LMW-HA fragments could in turn amplify or sustain the effect of the cytokine storm by stimulating the release of more cytokines from immune and alveolar cells leading to hyperinflammatory syndrome (Fig. 2).

Figure 2.

Schematic representation of known and suggested roles of HA in COVID-19 and ARDS. Viral infection may directly promote HA synthesis, and IL-13 is a known activator of HAS1 in COVID-19. Accumulation of HA promotes and sustains immune cell recruitment into the lung. Homeostatic HMW-HA becomes degraded by hyaluronidases in concert with reactive oxygen species by infiltrating neutrophils. Generation of LMW-HA fragments activate alveolar macrophages and induce the release of inflammatory cytokines (e.g., IL-6, IL-8, IL-10, and interferon-α), chemokines (e.g., IP-10 and MCP1), and growth factors by several cell types including alveolar epithelial cells. These proinflammatory LMW-HA fragments boost the effect of the cytokine storm by stimulating the release of more cytokines from immune and alveolar cells leading to hyperinflammatory syndrome. HA fragments generated during COVID-19 can directly promote endothelial barrier permeability. The edematous alveoli develop hypoxia as dysregulated HA synthesis and degradation proceed unchecked, leading to accumulation of HA within respiratory fluids, alveolar collapse, and ARDS. ARDS, acute respiratory distress syndrome; HA, hyaluronan; LMW-HA, low-molecular-weight hyaluronan.

Conclusions

In summary, these data describe HA as a unique and often-overlooked immune modulatory molecule, which contributes to homeostasis, inflammation, and repair. Through association with other binding partners, HA is endowed with a spectrum of protective properties that when dysregulated can contribute to edema and inflammation during infection, injury, or chronic disease. The pathogenesis of COVID-19 is yet to be fully understood, especially the fatal cases associated with ARDS. Present-day data reveal an emerging novel role of HA in lethal COVID-19 cases where it may contribute to cytokine storm, vascular manifestations, and respiratory dysfunction. Multiple lines of study in human subjects as well as animal models of respiratory and chronic inflammatory illness suggest that targeting HA as a treatment approach could be complementary to anti-inflammatory agents targeting cytokine storm in COVID-19 ARDS.

GRANTS

This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute Grant R00HL135265 (to A.C.P.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

This article is part of the special collection "Deciphering the Role of Proteoglycans and Glycosaminoglycans in Health and Disease." Liliana Schaefer, MD, served as Guest Editor of this collection.

AUTHOR CONTRIBUTIONS

N.A. prepared figures; N.A. drafted manuscript; N.A. and A.C.P. edited and revised manuscript; N.A. and A.C.P. approved final version of manuscript.