Barrier function of airway tract epithelium

Ganesan, Shyamala; Comstock, Adam T; Sajjan, Uma S

In addition to being a physical barrier, airway epithelium also acts as a biochemical barrier against invading pathogens. Airway epithelial cells secrete a wide variety of antimicrobial substances such as enzymes, protease inhibitors, oxidants, and antimicrobial peptides, which accumulates in the ASL and kill inhaled pathogens. Lysozyme, an enzyme found in airway epithelial secretions, exerts antimicrobial effect against a wide range of gram-positive bacteria by degrading their peptidoglycan layer. 131 Lysozyme is also effective against gram-negative bacteria in the presence of lactoferrin, which disrupts the outer membrane, allowing lysozyme to gain access to the peptidoglycan layer. 132 Lactoferrin is an iron-chelator and inhibits microbial growth by sequestering iron which is essential for microbial respiration. 133 Lactoferrin also displays antiviral activity against both RNA and DNA viruses by either inhibiting binding of the virus to host cells or by binding to the virus itself. 134, 135 Lactoferrin levels increase in response to bacterial and viral infections. In clinically stable COPD patients, lower levels of salivary lysozyme correlated with increased risk of exacerbations 136 while reduced lysozyme levels in COPD is thought to be due to degradation by proteases elaborated by bacterial pathogens or neutrophils. 137, 138 Epithelial cells produce protease inhibitors, such as secretory leukoprotease inhibitor (SLPI), elastase inhibitor, α1-antiprotease, and antichymotrypsin. These protease inhibitors mitigate the effects of proteases expressed by pathogens and recruited innate immune cells. Maintaining the balance between antiproteases and proteases in the airway lumen during infection is pivotal in preventing lung inflammation and maintenance of tissue homeostasis. In COPD patients, levels of SLPI and lysozyme were shown to decrease with bacterial infection, while lactoferrin levels remain unchanged. 139 This could be due to inactivation of SLPI by proteases or decreased expression of SLPI, but either way the end result under these conditions is an imbalance in the ratio of antiproteases to proteases in the airway lumen. Therefore, neutralization of proteases would be beneficial in this situation. Accordingly, administration of SLPI decreased the levels of IL-8 and elastase activity in airway secretion of cystic fibrosis patients, who also have reduced SLPI in their airway lumen. 140 Human β defensins (hBD) are the most abundant antimicrobial peptides expressed on the surface of airway epithelium and are effective against a wide range of bacteria and viruses. [141] [142] [143] While hBD1 is constitutively expressed, hBD2 to hBD4 expression is induced by LPS via NF-κB activation and by IL-1. 144, 145 hBD2 is induced by P. aeruginosa infection in normal but not in cystic fibrosis airway epithelia. 146 Activity of hBD2 is also attenuated in cystic fibrosis patients due to increased salt concentration. 147 Environmental factors such as air pollutants have e24997-6