Abstract
A high intrapulmonary protease burden is characteristic of cystic fibrosis (CF), and the resulting dysregulation of the protease/anti-protease balance has serious implications for inflammation in the CF lung. Because of this inflammation, micro-bleeds can occur releasing hemoglobin into the lung. The aim of this study was to investigate the effect of the protease-rich environment of the CF lung on human hemoglobin and to assess the proinflammatory effect of heme on CF bronchial epithelium. Here, we show that the Pseudomonas proteases (Pseudomonas elastase and alkaline protease) and the neutrophil proteases (neutrophil elastase (NE) and proteinase-3) are capable of almost complete degradation of hemoglobin in vitro but that NE is the predominant protease that cleaves hemoglobin in vivo in CF bronchoalveolar lavage fluid. One of the effects of this is the release of heme, and in this study we show that heme stimulates IL-8 and IL-10 protein production from ΔF508 CFBE41o(-) bronchial epithelial cells. In addition, heme-induced IL-8 expression utilizes a novel pathway involving meprin, EGF receptor, and MyD88. Meprin levels are elevated in CF cell lines and bronchial brushings, thus adding to the proinflammatory milieu. Interestingly, α(1)-antitrypsin, in addition to its ability to neutralize NE and protease-3, can also bind heme and neutralize heme-induced IL-8 from CFBE41o(-) cells. This study illustrates the proinflammatory effects of micro-bleeds in the CF lung, the process by which this occurs, and a potential therapeutic intervention.
Highlights
In the cystic fibrosis (CF) lung, proteases are secreted by the host and by bacteria that colonize the lung
Effect of Pseudomonas and Neutrophil Proteases on Hemoglobin—To examine if hemoglobin can be degraded by proteases found in the CF lung, hemoglobin was first incubated with the most abundant Pseudomonas proteases, Pseudomonas elastase (PsE) and alkaline protease (APR)
In addition to the bacterial proteases, a high concentration of the neutrophil proteases neutrophil elastase (NE), PR-3, and cathepsin G are present in the CF lung
Summary
In the CF lung, proteases are secreted by the host and by bacteria that colonize the lung. The most common bacteria to colonize the CF lung is P. aeruginosa, which is known to secrete the metalloproteases Pseudomonas elastase (PsE), alkaline protease (APR), and the less abundant staphylolysin. Pseudomonas like many bacteria requires iron for growth, and degradation of host iron-containing proteins is an excellent source of such iron Both the Pseudomonas proteases PsE and APR and the host protease NE are capable of cleaving transferrin and lactoferrin [7]. In addition to free iron, bacteria utilize heme, which can be released from hemoglobin. This is of particular significance in cystic fibrosis due to the frequent occurrence of micro-bleeds, which leads to the presence of hemoglobin at the delicate CF lung epithelia in the presence of both host and bacterial proteases. We assessed the inhibitory capacity of AAT against the heme-induced effects
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