Premedication with a cathepsin C inhibitor alleviates early primary graft dysfunction in mouse recipients after lung transplantation

Abstract

Neutrophil serine proteases (NSPs), like proteinase 3 (PR3) and neutrophil elastase (NE) are implicated in ischemia-reperfusion responses after lung transplantation (LTx). Cathepsin C (CatC) acts as the key regulator of NSP maturation during biosynthesis. We hypothesized that CatC inhibitors would reduce vascular breakdown and inflammation during reperfusion in pretreated lung transplant recipients by blocking NSP maturation in the bone marrow. An orthotopic LTx model in mice was used to mimic the induction of an ischemia-reperfusion response after 18 h cold storage of the graft and LTx. Recipient mice were treated subcutaneously with a chemical CatC inhibitor (ICatC) for 10 days prior to LTx. We examined the effect of the ICatC treatment by measuring the gas exchange function of the left lung graft, protein content, neutrophil numbers and NSP activities in the bone marrow 4 h after reperfusion. Pre-operative ICatC treatment of the recipient mice improved early graft function and lead to the disappearance of active NSP protein in the transplanted lung. NSP activities were also substantially reduced in bone marrow neutrophils. Preemptive NSP reduction by CatC inhibition may prove to be a viable and effective approach to reduce immediate ischemia reperfusion responses after LTx.

Lung Protection by Cathepsin C Inhibition: A New Hope for COVID-19 and ARDS?

“…Neutrophil elastase-related proteases are implicated in vascular compromise and inflammation following lung transplantation, the so-called ischemia–reperfusion response with primary graft dysfunction. 9 We hypothesized that IcatC XPZ-01 , by blocking elastase maturation in the bone marrow, might minimize this damage. We tested this in an orthotopic mouse lung transplantation (LTx) model after 18 h of cold storage of the graft.…”

“… 6 − 8 On the basis of the accumulated data from preclinical and clinical studies, neutrophils indeed play a crucial role in acute lung injury by releasing elastase-related serine proteases and reactive oxygen species under rapidly evolving deteriorating health conditions. 6 , 7 , 9 Decondensation of nuclear chromatin is promoted by neutrophil elastase released from primary granules and leads to neutrophil extracellular trap formation 10 which very recently has been inferred as a driver of severe COVID-19 pneumonia. 11 − 14 Neutrophil elastase-related serine proteases recognized as pharmacological targets in neutrophilic inflammatory diseases thus appear as promising targets of therapeutic intervention in COVID-19.…”

“…species under rapidly evolving deteriorating health conditions. 6,7,9 Decondensation of nuclear chromatin is promoted by neutrophil elastase released from primary granules and leads to neutrophil extracellular trap formation 10 which very recently has been inferred as a driver of severe COVID-19 pneumonia.…”

Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor

“…Significant anti-arthritic activity of IcatC XPZ‑01 can be observed in a monoclonal anti-collagen antibody-induced mouse model of rheumatoid arthritis . Pre-operative IcatC XPZ‑01 treatment of the recipient mice improved the early graft function and led to the disappearance of active NSP protein in the transplanted lung . In addition, the effective covalent kinase inhibitor (EGFR-derived inhibitor) reported by Zhang et al represents another discovery direction. , …”

“…32 Pre-operative IcatC XPZ-01 treatment of the recipient mice improved the early graft function and led to the disappearance of active NSP protein in the transplanted lung. 33 In addition, the effective covalent kinase inhibitor (EGFR-derived inhibitor) reported by Zhang et al represents another discovery direction. 21,34 Although Cys234 is the key amino acid for the Cat C function, there is no evidence pointing out that the introduction of an electrophilic "warhead" moiety is necessary.…”