Serine proteinase inhibitor therapy in α₁‐antitrypsin inhibitor deficiency and cystic fibrosis

Abstract

Proteinase‐antiproteinase imbalances are recognized in several diseases including the two most common lethal hereditary disorders of white populations, α1‐antitrypsin (α1‐AT) deficiency and cystic fibrosis (CF). In α1‐AT deficiency, the type Z variant of α1‐AT forms polymers in the endoplasmic reticulum of hepatocytes resulting in liver disease in childhood. The block in α1‐AT processing in hepatocytes significantly reduces levels of circulating α1‐AT. This may lead in young adults to panacinar emphysema due to insufficient protection of the lower respiratory tract from neutrophil elastase, permitting progressive destruction of the alveoli. In CF, chronic bacterial lung infections due to impaired mucociliary clearance lead to a vigorous influx of neutrophils in the airways. Released levels of neutrophil serine proteinases, particularly elastase, exceed the antiproteinase capacity of endogenous serine proteinase inhibitors in the airways. Progressive proteolytic impairment of multiple defense pathways in addition to endobronchial obstruction and airway wall destruction are thought to be responsible for the reduced life expectancy in CF patients. Strategies to augment the antiproteinase defenses in the airways of patients with severe α1‐AT deficiency or CF include the intravenous or aerosol administration of serine proteinase inhibitors. Studies in both patient groups using plasma‐derived or transgenic α1‐AT, recombinant secretory leukoprotease inhibitor or synthetic elastase inhibitors show promising results concerning drug safety and efficacy. Pediatr Pulmonol. 1999; 28:363–375. © 1999 Wiley‐Liss, Inc.

Neutrophil serine proteases fine-tune the inflammatory response

“…Nonetheless, these studies suggest that in vivo antagonism of serine protease activity may provide new therapeutic strategies in inflammatory diseases. Indeed, attempts have been made to suppress the activity of NE in hereditary emphysema (Dirksen et al, 1999;Doring, 1999), chronic obstructive pulmonary disease (COPD) (Luisetti et al, 1996;Ohbayashi, 2002), cystic fibrosis (Cantin et al, 2006;Doring, 1999;Martin et al, 2006), and the management of acute lung injury (Hoshi et al, 2005;Ono et al, 2007;Zeiher et al, 2004), all with varying results. To date, no inhibitors of serine proteases have been approved for use in patients as many practical problems associated with the synthesis and delivery of these agents still remain [Reviewed in (Chughtai and O'Riordan, 2004)].…”

Inhibition of Neutrophil Elastase by α1-Protease Inhibitor at the Surface of Human Polymorphonuclear Neutrophils

“…This is particularly important for developing antiinflammatory treatment for lung inflammatory diseases using inhibitors designed to target both free and membrane-bound forms of active proteases at inflammatory sites (19 -21). Several attempts have been made to treat patients with cystic fibrosis with aerosolized or inhaled inhibitors, but the results have not been conclusive partly due to their limited access to plugged areas (22)(23)(24). The partition of free and membrane-associated proteases in lung inflammatory secretions and their relative sensitivities to inhibitors appears to be an important factor influencing treatment design.…”

Revisiting 1-antitrypsin therapy in cystic fibrosis: can it still offer promise?

“…AAT is one of the most important protease inhibitors involved in confining tissue proteolysis during an inflammatory response [5]. Secreted by the liver, increased AAT concentrations are stimulated by interleukin (IL)-6 and it acts rapidly in the peripheral tissue to inhibit serine proteases, such as NE, cathepsin G and proteinase 3.…”