Elevated levels of neutrophil elastase in CPOD (Chronic Obstructive Pulmonary Disease) airways are regarded as the main trigger lung destruction and inflammation. SLPI (Secretory leukocyte protease inhibitor), an inhibitor protease, represents attractive candidate for treatment chronic diseases due to proteases excess. The antiprotease active site has been located on C-terminal domain. This stu...

Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of chronic airway diseases, including cystic fibrosis and chronic bronchitis. Neutrophils release elastase, a serine protease that impairs mucociliary clearance and stimulates goblet cell metaplasia and mucin production. We previously reported that neutrophil elastase increases expressi...

Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thiore...

The local balance between proteinase inhibitors and proteinases determines local proteolytic activity. Various studies have demonstrated the importance of serine proteinase inhibitors in regulating the activity of serine proteinases that are released by leucocytes during inflammation. Recently it has been shown that these inhibitors may also display functions that are distinct from those associ...

EPI-hNE4 is a highly specific and potent (Ki=4x10 M) inhibitor of human neutrophil elastase (hNE), currently under development at Debiopharm for the treatment of cystic fibrosis (CF). It has been engineered by means of a specific technology, “Directed Evolution of Novel Binding Proteins”, invented and patented by Dyax Corporation Cambridge, U.S. It is derived from the second Kunitz-type domain ...

Background: Neutrophils are part of our innate immune system. They are capable of accumulation in tissues, chemotaxis, phagocytosis and digests bacteria and fungi by their lysosymes. Yet, paradoxically neutrophils are mediators in acute liver injury. Extrahepatic biliary atresia (EHBA) is a progressive chronic cholangiopathy of infancy, even in those who undergo timely portoenterostomy. Objecti...

Chronic airway inflammation is an important feature of cystic fibrosis (CF), markedly influencing morbidity and mortality. We wanted to assess the contribution of the respiratory epithelium in the mediation of local inflammatory events, and, more particularly, its regulating role through cytokine secretion. We have studied the regulation of interleukin-6 and 8 (IL-6 and IL-8) production by the ...

Cardiopulmonary bypass, especially when prolonged, may result in hemostatic failure and pulmonary dysfunction, which has been attributed to changes in platelets and leukocytes, respectively. It has been well documented that contact of blood with synthetic surfaces causes platelet activation. In this report, we explore mechanisms of the activation of neutrophils during simulated in vitro extraco...

Activated polymorphonuclear neutrophils play an important role in the pathogenesis of vaso-occlusive painful sickle cell crisis. Upon activation, polymorphonuclear neutrophils can form neutrophil extracellular traps. Neutrophil extracellular traps consist of a meshwork of extracellular DNA, nucleosomes, histones and neutrophil proteases. Neutrophil extracellular traps have been demonstrated to ...

Elastase released from neutrophils as part of the innate immune system has been implicated in chronic diseases such as emphysema and cardiovascular disease. We have previously shown that neutrophil elastase targets vascular endothelial growth factor-A (VEGF) for partial degradation to generate a fragment of VEGF (VEGFf) that has distinct activities. Namely, VEGFf binds to VEGF receptor 1 but no...