The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome

Cesta, Maria Candida; Zippoli, Mara; Marsiglia, Carolina; Gavioli, Elizabeth Marie; Mantelli, Flavio; Allegretti, Marcello; Balk, R.A.

doi:10.3389/fphar.2021.808797

Cited by 84 publications

(78 citation statements)

References 76 publications

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“…Although all these preliminary studies were performed with a limited number of patient samples, our findings agree with these reports, demonstrating robust production of the neutrophilchemoattractant chemokine CXCL8 as a universal COVID-19 mediator in systemic and airway compartments. Thus, the present and previous finds are indicative that CXCL8-neutrophil axis would be a putative target for therapeutic interventions (26).…”

Section: Discussionsupporting

confidence: 66%

“…Significant elevation of CXCL8, which is a classic neutrophil activation and chemoattractant mediator indicates the presence of these polymorphonuclear cells as pivotal driver of the immunopathogenesis in COVID-19 (14,(25)(26)(27)(28)(29). In line with this hypothesis, neutrophils have been found as important conspirators of morbid thrombotic events and severe COVID-19 by the formation of neutrophil extracellular traps (NETs) (28).…”

Section: Discussionmentioning

confidence: 87%

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Timeline Kinetics of Systemic and Airway Immune Mediator Storm for Comprehensive Analysis of Disease Outcome in Critically Ill COVID-19 Patients

et al. 2022

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In the present study, the levels of serum and airway soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were quantified in critically ill COVID-19 patients (total n=286) at distinct time points (D0, D2-6, D7, D8-13 and D>14-36) upon Intensive Care Unit (ICU) admission. Augmented levels of soluble mediators were observed in serum from COVID-19 patients who progress to death. An opposite profile was observed in tracheal aspirate samples, indicating that systemic and airway microenvironment diverge in their inflammatory milieu. While a bimodal distribution was observed in the serum samples, a unimodal peak around D7 was found for most soluble mediators in tracheal aspirate samples. Systems biology tools further demonstrated that COVID-19 display distinct eccentric soluble mediator networks as compared to controls, with opposite profiles in serum and tracheal aspirates. Regardless the systemic-compartmentalized microenvironment, networks from patients progressing to death were linked to a pro-inflammatory/growth factor-rich, highly integrated center. Conversely, patients evolving to discharge exhibited networks of weak central architecture, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. All in all, this investigation with robust sample size landed a comprehensive snapshot of the systemic and local divergencies composed of distinct immune responses driven by SARS-CoV-2 early on severe COVID-19.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 87%

Timeline Kinetics of Systemic and Airway Immune Mediator Storm for Comprehensive Analysis of Disease Outcome in Critically Ill COVID-19 Patients

et al. 2022

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“…Because lack of therapeutic options for tackling acute respiratory distress syndrome (ARDS) in COVID-19 patients, attention has now focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help develop effective therapeutic interventions. In this regard, IL-8 which is a pro-inflammatory cytokine performs an important role in neutrophil activation and has been identified for the progression of COVID-19 disease [ 83 , 84 ]. Furthermore, it has been reported that COVID-19 patients with severe outcome also display higher plasma levels of chemokines such as CXCL9/MIG, CXCL8/IL-8, and CXCL10/IP10 along with cytokines IL-6 and IL-10 than the patients with the milder form of the COVID-19 [ 85 ].…”

Section: Resultsmentioning

confidence: 99%

Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers

et al. 2022

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The ongoing pandemic (also known as coronavirus disease-19; COVID-19) by a constantly emerging viral agent commonly referred as the severe acute respiratory syndrome corona virus 2 or SARS-CoV-2 has revealed unique pathological findings from infected human beings, and the postmortem observations. The list of disease symptoms, and postmortem observations is too long to mention; however, SARS-CoV-2 has brought with it a whole new clinical syndrome in “long haulers” including dyspnea, chest pain, tachycardia, brain fog, exercise intolerance, and extreme fatigue. We opine that further improvement in delivering effective treatment, and preventive strategies would be benefited from validated animal disease models. In this context, we designed a study, and show that a genetically engineered mouse expressing the human angiotensin converting enzyme 2; ACE-2 (the receptor used by SARS-CoV-2 agent to enter host cells) represents an excellent investigative resource in simulating important clinical features of the COVID-19. The ACE-2 mouse model (which is susceptible to SARS-CoV-2) when administered with a recombinant SARS-CoV-2 spike protein (SP) intranasally exhibited a profound cytokine storm capable of altering the physiological parameters including significant changes in cardiac function along with multi-organ damage that was further confirmed via histological findings. More importantly, visceral organs from SP treated mice revealed thrombotic blood clots as seen during postmortem examination. Thus, the ACE-2 engineered mouse appears to be a suitable model for studying intimate viral pathogenesis thus paving the way for identification, and characterization of appropriate prophylactics as well as therapeutics for COVID-19 management.

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“…This evidence suggests that, in LAM, senescent LAM cells might reduce the proliferation of lung resident cells and, at the same time, might promote a pro-inflammatory microenvironment that ultimately has detrimental effects on the lung tissue. Indeed, even if IL-8 has a clear role as a SASP molecule, its secretion by fibroblasts, alveolar macrophages, and alveolar cells and its involvement in neutrophil migration and infiltration in lungs suggest a more complex physiological implication, making the deregulation of IL-8 secretion responsible for pathological processes, i.e., in IPF [25], acute respiratory distress syndrome [26], and chronic obstructive pulmonary disease [39]. Besides the crucial role of IL-8 in lung inflammation, little is known concerning its involvement in LAM or TSC.…”

Section: Discussionmentioning

confidence: 99%

“…IL-8 is a chemokine overexpressed in the most senescent cells as a SASP component and its high levels in lung parenchyma have been related to the pathogenesis and progression of lung diseases, such as IPF [25]. IL-8 is expressed in various cell types, including fibroblasts, and is highly secreted by LAM/TSC cells [16,26]. The mRNA relative expression and the secretion of IL-8 were significantly higher in LAM/TSC cells compared to PLFs suggesting a SASP IL-8 role in sustaining LAM/TSC cell senescent phenotype (Figure 7a,c).…”

Section: Evaluation Of Il-8 Expression and Secretion In Plfs Lam/tsc ...mentioning

confidence: 99%

LAM Cells as Potential Drivers of Senescence in Lymphangioleiomyomatosis Microenvironment

Bernardelli

Ancona

Lazzari

et al. 2022

IJMS

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Senescence is a stress-response process characterized by the irreversible inhibition of cell proliferation, associated to the acquisition of a senescence-associated secretory phenotype (SASP), that may drive pathological conditions. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells, featuring the hyperactivation of the mammalian Target of Rapamycin Complex 1 (mTORC1) for the absence of tuberin expression, cause the disruption of the lung parenchyma. Considering that LAM cells secrete SASP factors and that mTOR is also a driver of senescence, we deepened the contribution of senescence in LAM cell phenotype. We firstly demonstrated that human primary tuberin-deficient LAM cells (LAM/TSC cells) have senescent features depending on mTOR hyperactivation, since their high positivity to SA-β galactosidase and to phospho-histone H2A.X are reduced by inducing tuberin expression and by inhibiting mTOR with rapamycin. Then, we demonstrated the capability of LAM/TSC cells to induce senescence. Indeed, primary lung fibroblasts (PLFs) grown in LAM/TSC conditioned medium increased the positivity to SA-β galactosidase and to phospho-histone H2A.X, as well as p21WAF1/CIP1 expression, and enhanced the mRNA expression and the secretion of the SASP component IL-8. Taken together, these data make senescence a novel field of study to understand LAM development and progression.

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The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome

Cited by 84 publications

References 76 publications

Timeline Kinetics of Systemic and Airway Immune Mediator Storm for Comprehensive Analysis of Disease Outcome in Critically Ill COVID-19 Patients

Timeline Kinetics of Systemic and Airway Immune Mediator Storm for Comprehensive Analysis of Disease Outcome in Critically Ill COVID-19 Patients

Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers

LAM Cells as Potential Drivers of Senescence in Lymphangioleiomyomatosis Microenvironment

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