Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury

A Functional Variant of Elafin With Improved Anti-inflammatory Activity for Pulmonary Inflammation

“…A number of pathogen and host proteases have the ability to cleave elafin. [25][26][27][28] Increased NE activity is present in various respiratory diseases including ARDS, COPD, and CF and may overwhelm the protective antiprotease levels within the lung. Indeed, we have found evidence of proteolytic cleavage of elafin by NE in patients with CF with established Pseudomonas aeruginosa infection.…”

“…29 An imbalance in NE and trappin-2/elafin levels has also been reported in ARDS and COPD patients with secondary bacterial infections. 26,30,31 In early 2013, the US Food and Drug Administration (FDA) granted elafin orphan drug designation for the prevention of inflammatory complications associated with transthoracic esophagectomy. 32 However, proteolytic cleavage of elafin could attentuate its anti-inflammatory and antiprotease functions and limit the efficacy of elafin in clinical trials in conditions such as ARDS, CF, and COPD.…”

A role for whey acidic protein four-disulfide-core 12 (WFDC12) in the regulation of the inflammatory response in the lung

“…The levels of WFDC12 in ARDS BALF were slightly lower than, but still comparable with, that of SLPI and elafin. WFDC12 was detected at 13.6 (±1.2) ng/mL, equivalent to 1.24 (±0.11) nM; we have previously reported nanomolar levels of SLPI (approximately 8.75 nM) and elafin (approximately 5.11 nM) in BALF from patients with ARDS 25. The significantly elevated levels of WFDC12 (relative to healthy controls) found in BALF from patients with ARDS and healthy volunteers post LPS-inhalation may represent an upregulation and/or increased secretion of WFDC12 from epithelial and immune cells as part of the acute response to inflammation.…”

“…However, deposition of the protein to poorly ventilated areas of the CF lung was later shown to be not wholly efficient 30. In addition, it is now known that both SLPI and elafin are prone to proteolytic cleavage by the excessive levels of proteases associated with dysregulated inflammation,25 31 perhaps limiting their full therapeutic capacity. Therefore, WFDC12 should ideally be examined for similar susceptibility before investigation as a possible therapy.…”

Year in review 2013: basic science and epidemiology

“…Proteolytic cleavage of the naturally occurring protein elafin by the 20S proteasome may account for the observed decrease in elafin observed over the course of acute lung injury and predispose people to excessive inflammatory responses 4. Similarly, circulating neutrophils from patients with COPD showed reduced chemotactic activity and capacity for bacterial killing due to the presence of elastin peptides, released as a result of proteases released from lung-infiltrating neutrophils 5.…”