Fig 1 - available via license: CC BY
Content may be subject to copyright.
![Compartmentalized hyaluronic acid levels are differentially associated with measures of local and systemic organ injury. Elevated alveolar levels of hyaluronic acid are associated with lung injury score (LIS) (a) but not sequential organ failure assessment (SOFA) score (b), while circulating levels are associated with both (c, d). [HA], concentration of hyaluronic acid. β values represent a change in units of either LIS (a, b) or SOFA (c, d) score per tenfold increase in [HA]. Solid lines represent regression lines determined via linear regression analyses, while hashed lines represent the 95% confidence interval of the regression line](publication/321767077/figure/fig1/AS:573451543236608@1513732910877/Compartmentalized-hyaluronic-acid-levels-are-differentially-associated-with-measures-of.png)
Compartmentalized hyaluronic acid levels are differentially associated with measures of local and systemic organ injury. Elevated alveolar levels of hyaluronic acid are associated with lung injury score (LIS) (a) but not sequential organ failure assessment (SOFA) score (b), while circulating levels are associated with both (c, d). [HA], concentration of hyaluronic acid. β values represent a change in units of either LIS (a, b) or SOFA (c, d) score per tenfold increase in [HA]. Solid lines represent regression lines determined via linear regression analyses, while hashed lines represent the 95% confidence interval of the regression line
Source publication
Background:
Hyaluronic acid (HA), an extracellular matrix component, is degraded in response to local tissue injury or stress. In various animal models of lung injury, HA has been shown to play a mechanistic role in modulating inflammation and injury. While HA is present in the lungs of patients with acute respiratory distress syndrome (ARDS), its...
Contexts in source publication
Context 1
... for associations between HA levels in serum and BALF and measures of local lung injury severity. Considering the concentration of HA at study enroll- ment (day 0) and adjusting for age, sex, race, treatment group, and ARDS risk factor, a tenfold increase in day-0 serum HA concentration was associated with an increase of 0.30 in LIS (p = 0.04; Fig. 1a and Table 2). A tenfold increase in BALF HA concentration was associated with a 0.27 increase in LIS (p = 0.003; Fig. 1b and Table 2). Both serum and BALF HA levels were associated with severity of ARDS as defined by the Berlin criteria (p = 0.001; Additional file 4). Neither serum (p = 0.14) nor BALF (p = 0.47) HA levels were ...
Context 2
... of HA at study enroll- ment (day 0) and adjusting for age, sex, race, treatment group, and ARDS risk factor, a tenfold increase in day-0 serum HA concentration was associated with an increase of 0.30 in LIS (p = 0.04; Fig. 1a and Table 2). A tenfold increase in BALF HA concentration was associated with a 0.27 increase in LIS (p = 0.003; Fig. 1b and Table 2). Both serum and BALF HA levels were associated with severity of ARDS as defined by the Berlin criteria (p = 0.001; Additional file 4). Neither serum (p = 0.14) nor BALF (p = 0.47) HA levels were associated with quartile of VFDs (Table ...
Context 3
... tested for associations between HA and systemic measures of organ dysfunction. Considering the concentration of HA at study enrollment (day 0) and adjusting for age, sex, race, treatment group, and ARDS risk factor, we found that a tenfold increase in serum HA concentration was associated with an increase of 4 points in SOFA score (p < 0.001; Fig. 1c and Table 2). BALF HA concentration was not associated with increasing SOFA score (p = 0.27; Fig. 1d and Table 2). Neither serum HA (p = 0.21) nor BALF HA (p = 0.32) concentration were associated with 28-day mortality (Additional file ...
Context 4
... of HA at study enrollment (day 0) and adjusting for age, sex, race, treatment group, and ARDS risk factor, we found that a tenfold increase in serum HA concentration was associated with an increase of 4 points in SOFA score (p < 0.001; Fig. 1c and Table 2). BALF HA concentration was not associated with increasing SOFA score (p = 0.27; Fig. 1d and Table 2). Neither serum HA (p = 0.21) nor BALF HA (p = 0.32) concentration were associated with 28-day mortality (Additional file ...
Citations
... Despite their modest association, it supports positive feedback between inflammation and fibrosis (Su et al., 2017). HA, produced by fibroblasts and connective-tissue cells, is a mucopolysaccharide that forms the extracellular matrix and is a major component of the alveolar extracellular matrix that promotes lung interstitial development (Morales-Nebreda et al., 2015;Esposito et al., 2017). In response to various viral and inflammatory stimuli, the increase of hyaluronic acid reflects the process of lung fibrosis. ...
Background
The coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving global emergency and continuously poses a serious threat to public health, highlighting the urgent need of identifying biomarkers for disease severity and progression. In order to early identify severe and critical patients, we retrospectively analyze the clinical characteristics and risk indicators of severe disease in patients with corona virus disease 2019 (COVID-19).
Methods
A total of 420 confirmed COVID-19 patients were included in the study. According to the “Diagnosis and Treatment of novel coronavirus Pneumonia (10th Edition)”, the cases were divided into mild group (n = 243) and severe group (n =177). Laboratory parameters were analyzed in combination with clinical data.
Results
Male patients over 46 years who have smoking habits were more likely to suffer from severe COVID-19. Critically ill patients had lower lymphocyte counts and red blood cell counts, and higher white blood cell counts (P<0.05). Expectedly, serum inflammatory factors (NLR, PLR, LMR, CLR, PCT, CRP), coagulation markers (APTT, PT, TT, FIB, D-Dimer), Myocardial damage markers (hs-TNT, LDH) were significantly increased (P<0.05) in severe COVID-19 patients. Surprisedly, those patients showed obviously elevated levels of common tumor markers (ProGRP, CYFRA21-1, SCC, NSE) (P<0.05). In this case, the levels of tumor marker reflected more the condition of inflammation than the growth of tumor. More importantly, HA and PIIIN-P were highly associated with COVID-19 severity. The AUC of the ROC curve for the diagnosis of severe COVID-19 by HA and PIIIN-P was 0.826. Meanwhile, HA was positively correlated with myocardial damage markers (hs-TNT, LDH). PIIIN-P was positively correlated with myocardial damage markers (hs-TNT, LDH) and inflammatory factors (NLR, PLR, LMR, CLR, ProGRP, SCC, PCT, CRP). On the contrary, PIIIN-P was negatively correlated with pulmonary function indexes (oxygenation index and oxygen saturation of hemoglobin).
Conclusion
HA and PIIIN-P are highly associated with disease severity and progression of COVID-19 and can be used as new markers for the prediction of severe COVID-19.
... Despite intensive studies, the complex pathogenesis and variable progression result in a median survival of only 3-5 years after diagnosis [5]. The bleomycin (BLM)-induced model of acute lung injury represents the most widely used experimental rodent model for this disease, and simulates inflammatory and fibrotic events similar to pulmonary fibrosis symptoms seen clinically [6][7][8][9]. BLM exposure results in release of inflammatory mediators and promotes initial inflow from neutrophils and, subsequently macrophages to sites of injury, with commensurate rises in ECM modulation and cytokine production including collagen, fibronectin, and hyaluronan [10]. ...
Background:
Pulmonary fibrosis (PF), the most common clinical type of irreversible interstitial lung disease with one of the worse prognoses, has a largely unknown molecular mechanisms that underlies its progression. CD5 molecule-like (CD5L) functions in an indispensable role during inflammatory responses; however, whether CD5L functions in regulating bleomycin (BLM)-induced lung fibrosis is less clear.
Methods:
Herein, we describe the engineering of Cd5l knockout mice using CRISPR/Cas9 gene editing technology. The BLM-induced model of acute lung injury represents the most widely used experimental rodent model for PF.
Results:
Taking advantage of this model, we demonstrated that both CD5L mRNA and protein were enriched in the lungs of mice following BLM-induced pulmonary fibrosis. Inhibition of CD5L prevented mice from BLM-induced lung fibrosis and injury. In particular, a lack of CD5L significantly attenuated inflammatory response and promoted M2 polarization in the lung of this pulmonary fibrosis model as well as suppressing macrophage apoptosis.
Conclusions:
Collectively, our data support that CD5L deficiency can suppress the development of pulmonary fibrosis, and also provides new molecular targets for the use of immunotherapy to treat lung fibrosis.
... 6 In this study, we used human SOD1 (hSOD1), a copperzinc metalloenzyme found in the cytoplasm and nucleus. 7 As elevated levels of hyaluronic acid (HA) are associated with many lung diseases, including ARDS, 8 we produced protein with a fused HA-binding peptide to increase lung residence time. ...
Background: Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome with diverse etiologies characterized by increased permeability of alveolar-capillary membranes, pulmonary edema, and acute onset hypoxemia. During the ARDS acute phase, neutrophil infiltration into the alveolar space results in uncontrolled release of reactive oxygen species (ROS) and proteases, overwhelming antioxidant defenses and causing alveolar epithelial and lung endothelial injury. Objectives: To investigate the therapeutic potential of a novel recombinant human Cu-Zn-superoxide dismutase (SOD) fusion protein in protecting against ROS injury and for aerosolized SOD delivery to treat Escherichia coli induced ARDS. Methods: Fusion proteins incorporating human Cu-Zn-SOD (hSOD1), with (pep1-hSOD1-his) and without (hSOD1-his) a fused hyaluronic acid-binding peptide, were expressed in E. coli. Purified proteins were evaluated in in vitro assays with human bronchial epithelial cells and through aerosolized delivery to the lung of an E. coli-induced ARDS rat model. Results: SOD proteins exhibited high SOD activity in vitro and protected bronchial epithelial cells from oxidative damage. hSOD1-his and pep1-hSOD1-his retained SOD activity postnebulization and exhibited no adverse effects in the rat. Pep1-hSOD1-his administered through instillation or nebulization to the lung of an E. coli-induced pneumonia rat improved arterial oxygenation and lactate levels compared to vehicle after 48 hours. Static lung compliance was improved when the pep1-hSOD1-his protein was delivered by instillation. White cell infiltration to the lung was significantly reduced by aerosolized delivery of protein, and reduction of cytokine-induced neutrophil chemoattractant-1, interferon-gamma, and interleukin 6 pro-inflammatory cytokine concentrations in bronchoalveolar lavage was observed. Conclusions: Aerosol delivery of a novel recombinant modified SOD protein reduces oxidant injury and attenuates E. coli induced lung injury in rats. The results provide a strong basis for further investigation of the therapeutic potential of hSOD1 in the treatment of ARDS.
... HA is also implicated in ARDS [79,80]. Ventilatorinduced lung injury promotes the synthesis of LMW-HA via HAS3 upregulation in fibroblasts, leading to increased inflammatory cell infiltration, vascular leak, and both interstitial and alveolar edema [81]. ...
... In combination with alveolar collapse, this contributes to the ventilation-perfusion mismatch, hypoxia, and respiratory failure seen in ARDS. HA levels in bronchoalveolar lavage fluid are associated with organ failure in ARDS [79] and there is an inverse correlation between the concentration of HA (BAL and serum) and the pulmonary oxygenation index in patients with ARDS [82,83]. Using experimental models of ARDS, investigators have demonstrated that inhibition of HA reduced markers of cell injury [84,85]. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. Then we briefly summarize the known roles of HA in airway inflammation and immunity. We then address what is known about HA and the pathogenesis of COVID-19 acute respiratory distress syndrome (COVID-19 ARDS). Next, we examine potential roles for HA in post-acute SARS-CoV-2 infection (PASC), also known as "long COVID" as well as in COVID-associated fibrosis. Finally, we discuss the potential therapeutics that target HA as a means to treat COVID-19, including the repurposed drug hymecromone (4-methylumbelliferone). We conclude that HA is a promising potential therapeutic target for the treatment of COVID-19.
... In the last stage, fibrosis of granulation tissue is accompanied by deposition of extracellular matrix proteins. Then, reorganization of connective tissue and vessels leads to the scar formation [7][8][9]. Nowadays ALI is widely regarded to associate with COVID-19. In the disease, SARS-COV-2 infects the lung by attaching to angiotensin-converting enzyme and causes a series of related symptoms, including alveolar injury, abnormal vasculature, and pulmonary edema, as verified through postmortem examination [10]. ...
Acute lung injury (ALI) describes the injury to endothelial cells in the lungs and associated vessels due to various factors. Furthermore, ALI accompanied by inflammation and thrombosis has been reported as a common complication of SARS-COV-2 infection. It is widely accepted that inflammation and the cytokine storm are main causes of ALI. Two classical anti-inflammatory cell types, regulatory T cells (Tregs) and M2 macrophages, are theoretically capable of resisting uncontrolled inflammation. Recent studies have indicated possible crosstalk between Tregs and macrophages involving their mutual activation. In this review, we discuss the current findings related to ALI pathogenesis and the role of Tregs and macrophages. In particular, we review the molecular mechanisms underlying the crosstalk between Tregs and macrophages in ALI pathogenesis. Understanding the role of Tregs and macrophages will provide the potential targets for treating ALI.
... BAL measurement of N-terminal peptide of alveolar procollagen type III, a precursor of collagen type III, has been validated as a diagnostic tool to indicate fibroproliferation in ARDS patients as well as to identify patients who can benefit from corticosteroid treatment (Forel et al., 2015;Hamon et al., 2019). Serological and BAL levels of hyaluronic acid were found associated with ARDS severity and organ failure (Esposito et al., 2017). Recently, lung tissue obtained from patients with coronavirus disease (COVID-19) induced ARDS, stained positively for hyaluronic acid which was associated with the degree of alveolar damage (Hellman et al., 2020). ...
Environmental insults including respiratory infections, in combination with genetic predisposition, may lead to lung diseases such as chronic obstructive pulmonary disease, lung fibrosis, asthma, and acute respiratory distress syndrome. Common characteristics of these diseases are infiltration and activation of inflammatory cells and abnormal extracellular matrix (ECM) turnover, leading to tissue damage and impairments in lung function. The ECM provides three-dimensional (3D) architectural support to the lung and crucial biochemical and biophysical cues to the cells, directing cellular processes. As immune cells travel to reach any site of injury, they encounter the composition and various mechanical features of the ECM. Emerging evidence demonstrates the crucial role played by the local environment in recruiting immune cells and their function in lung diseases. Moreover, recent developments in the field have elucidated considerable differences in responses of immune cells in two-dimensional versus 3D modeling systems. Examining the effect of individual parameters of the ECM to study their effect independently and collectively in a 3D microenvironment will help in better understanding disease pathobiology. In this article, we discuss the importance of investigating cellular migration and recent advances in this field. Moreover, we summarize changes in the ECM in lung diseases and the potential impacts on infiltrating immune cell migration in these diseases. There has been compelling progress in this field that encourages further developments, such as advanced in vitro 3D modeling using native ECM-based models, patient-derived materials, and bioprinting. We conclude with an overview of these state-of-the-art methodologies, followed by a discussion on developing novel and innovative models and the practical challenges envisaged in implementing and utilizing these systems.
... Hyaluronic acid (HA) or hyaluronan, a polysaccharide synthesized by a class of integral membrane hyaluronan synthases of stromal cells and deposited in the extracellular matrix (ECM), is closely involved with the pathophysiology of ARDS [5,[11][12][13]. Following lung injury, aberrant HA production from mast cells, epithelial cells, endothelial cells, and fibroblasts leads to excess HA accumulation in the airway lumen, thickened perialveolar interstitium, and alveolar obstruction, thereby reducing lung compliance and ventilation [2,[14][15][16][17]. ...
... Following lung injury, aberrant HA production from mast cells, epithelial cells, endothelial cells, and fibroblasts leads to excess HA accumulation in the airway lumen, thickened perialveolar interstitium, and alveolar obstruction, thereby reducing lung compliance and ventilation [2,[14][15][16][17]. Small HA fragments generated by multiple mechanisms in the exudative phase of ARDS are actively involved in signaling pathways of the cytokine release syndrome (CRS) or so-called cytokine storm that manifest systemic immune-mediated processes, fever, and multi-organ dysfunction [5,7,11,12,18,19]. The small HA fragments and oligosaccharides serve as Toll-like receptors (TLRs) agonists to initiate inflammatory cascades that promote inflammatory cell recruitment and activation. ...
Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system.
Methods
HA of 10 kDa molecular weight (HA10) was radiolabeled with ¹²⁵I and 99mTc respectively to produce [¹²⁵I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS.
Results
[99mTc]Tc-HA10 and [¹²⁵I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining.
Conclusions
[99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS.
... RHAMM is implicated in acute lung injury (101), and alcohol use exacerbates acute lung injury (4,8,13,102,103). However, it is not yet known how alcohol consumption directly affects RHAMM in any organ system. ...
Although the epidemiology of bacterial pneumonia and excessive alcohol use is well established, the mechanisms by which alcohol induces risk of pneumonia are less clear. Patterns of alcohol misuse, termed alcohol use disorders (AUD), affect about 15 million people in the United States. Compared to otherwise healthy individuals, AUD increase the risk of respiratory infections and acute respiratory distress syndrome (ARDS) by 2-4-fold. Levels and fragmentation of hyaluronic acid (HA), an extracellular glycosaminoglycan of variable molecular weight, are increased in chronic respiratory diseases, including ARDS. HA is largely involved in immune-assisted wound repair and cell migration. Levels of fragmented, low molecular weight HA are increased during inflammation and decrease concomitant with leukocyte levels following injury. In chronic respiratory diseases, levels of fragmented HA and leukocytes remain elevated, inflammation persists, and respiratory infections are not cleared efficiently, suggesting a possible pathological mechanism for prolonged bacterial pneumonia. However, the role of HA in alcohol-induced immune dysfunction is largely unknown. This mini literature review provides insights into understanding the role of HA signaling in host immune defense following excessive alcohol use. Potential therapeutic strategies to mitigate alcohol-induced immune suppression in bacterial pneumonia and HA dysregulation are also discussed.
... In the lung specifically, HA accumulation is associated with a number of inflammatory diseases (14)(15)(16)(17)(18)(19). HA is elevated in the bronchoalveolar lavage (BAL) fluid of patients suffering from chronic obstructive pulmonary disease (COPD) (20), interstitial pulmonary fibrosis (IPF) (21), and acute respiratory distress syndrome (ARDS) (22)(23)(24)(25)(26)(27). In these settings, HA stimulates a proinflammatory cascade (28) and contributes to respiratory pathophysiology, including fluid accumulation, airway plugging, and impaired oxygen exchange (29)(30)(31). ...
... Given that a more dramatic response was observed in participants with a higher baseline HA concentration, even at these relatively low HA concentrations, we hypothesize that hymecromone will have a meaningful effect in patients with pathologically elevated HA significantly higher than the healthy population. In disease states, HA concentrations are frequently elevated hundreds to several thousand times the normal range (22)(23)(24)(25)(26)(27)65). It is therefore plausible that individuals with disease might demonstrate a greater absolute response. ...
BACKGROUND
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODS
We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSION
After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.
... 23 Notably, hyaluronan is accumulated in the bronchoalveolar lavage fluid (BALF) and serum samples of patients with ARDS. 24 We also found that hyaluronan was significantly correlated with lymphocytes, CRP, D-dimer, and fibrinogen. These clinical indicators are proven biomarkers for the clinical progression of COVID-19. ...
Currently, there is no effective drugs for treating clinically COVID-19 except dexamethasone. We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid (HA). As the inhibitor of HA synthesis, hymecromone is an approved prescription drug used for treating biliary spasm. Here, we aimed to investigate the relation between HA and COVID-19, and evaluate the therapeutic effects of hymecromone on COVID-19. Firstly, HA was closely relevant to clinical parameters, including lymphocytes (n = 158; r = −0.50; P < 0.0001), C-reactive protein (n = 156; r = 0.55; P < 0.0001), D-dimer (n = 154; r = 0.38; P < 0.0001), and fibrinogen (n = 152; r = 0.37; P < 0.0001), as well as the mass (n = 78; r = 0.43; P < 0.0001) and volume (n = 78; r = 0.41; P = 0.0002) of ground-glass opacity, the mass (n = 78; r = 0.48; P < 0.0001) and volume (n = 78; r = 0.47; P < 0.0001) of consolidation in patient with low level of hyaluronan (HA < 48.43 ng/mL). Furthermore, hyaluronan could directly cause mouse pulmonary lesions. Besides, hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression. Moreover, 89% patients with hymecromone treatment had pulmonary lesion absorption while only 42% patients in control group had pulmonary lesion absorption (P < 0.0001). In addition, lymphocytes recovered more quickly in hymecromone-treated patients (n = 8) than control group (n = 5) (P < 0.05). These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.
