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Heterogeneous neutrophils in lung transplantation and proteolytic CXCL8 activation in COVID-19, influenza and lung transplant patient lungs. | LitMetric

AI Article Synopsis

  • * The study found significant diversity in neutrophil maturity levels, but the activation phenotype was consistent, with potent and partially inactivated forms of the chemokine CXCL8 identified that are linked to increased neutrophil activity.
  • * The research suggests that using protease inhibitors to lessen the rapid breakdown of CXCL8 may help control excessive inflammation and tissue damage in lung transplant patients.

Article Abstract

Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH-terminally truncated proteoforms CXCL8(6-77), CXCL8(8-77) and CXCL8(9-77), but also the partially inactivated CXCL8(10-77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9-77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615237PMC
http://dx.doi.org/10.1007/s00018-024-05500-zDOI Listing

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