Respiratory illnesses affect over two-thirds of Veterans deployed to Iraq or Afghanistan. The fact that respiratory tract disorders are among the most common medical conditions in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) Veterans has been a consistent finding that affects military personnel regardless of age, rank, gender or active duty/National Guard status. Nearly 23% of OEF/OIF Veterans felt unit effectiveness was negatively affected by respiratory illnesses1. Even minor upper respiratory tract infections are known to have a significant impact on military operations2 and concern has been raised about a possible increase in frequency of respiratory tract infections and allergy among personnel deployed to Iraq1. Our Veterans experience an increased number of environmental exposures that likely contribute to these inflammatory respiratory conditions, to include tobacco smoke and diesel exhaust. Nearly half of OEF/OIF Veterans started or re-started smoking during deployment. Additionally, exposure to diesel exhaust particles (DEP) occurs from the extensive use of diesel engines in military vehicles and equipment. Both tobacco smoke and DEP are known airborne toxins that cause extensive oxidative inflammation due to free radicals and can lead to exacerbation of allergic rhinitis3. Quick degradation of free radicals results in reactive oxygen species (ROS)4-6. Antioxidant enzymes that metabolize ROS, thus serve as potential therapeutic agents. These antioxidants include superoxide dismutase (SOD), which converts superoxide, one of the most toxic ROS, to much less reactive peroxide, and catalase (CAT), which converts peroxide into water and oxygen. One problem with therapeutic use of antioxidants is ensuring that topically administered agents remain in contact with the respiratory mucosa long enough to be effective. Normal mucociliary clearance removes topical medications from the respiratory tract within 15-20 minutes when it would be more desirable to maintain mucosal contact for hours to days. We propose to achieve targeted delivery to and retention of SOD and CAT (antioxidants) on respiratory epithelium using biodegradable polylactic acid (PLA) nanoparticles (NPs). We will simultaneously coat NPs with SOD and/or CAT and a targeting antibody (Ab) to mucin 1 (MUC1), which binds to the luminal surface of airway epithelial cells. Our preliminary studies demonstrate that HSNECs play a critical role in modulating the inflammatory response to environmental stimuli, and that targeting HSNECs with antioxidants can favorably impact the subsequent APC and T cell responses. Our central hypothesis is that smoke and DEP exposure experienced by OEF/OIF Veterans impacts HSNEC-APC communication via ROS and that this inflammatory response can be ameliorated through the use of antioxidant nanoparticles targeted at the respiratory epithelium. This hypothesis will be tested by the following specific aims:
Specific Aim 1 : To determine binding characteristics and epithelial toxicity of antibody-antioxidant- NPs. SOD and CAT will be covalently attached to PLA NPs simultaneously with antiMUC1 Ab. NPs with different ratios of SOD, CAT and antiMUC1 will be prepared and effects of the SOD:CAT:antiMUC1 ratios upon binding characteristics, function and toxicity will be evaluated in vitro using HSNEC cultures.
Specific Aim 2 : To determine in vitro efficacy of antioxidant NPs in inhibiting smoke and DEP induced inflammation. We will use optimized antiMUC1-SOD/CAT-NPs identified in Aim 1 to determine efficacy and ability to prevent smoke and DEP induced in vitro inflammatory response in HSNECs and APCs as the initial steps in the immune response.
Specific Aim 3 : To determine in vivo efficacy of antioxidant NPs on smoke and DEP exacerbated rhinosinusitis. We will use a murine model of allergic fungal rhinosinusitis with exacerbation by smoke or DEP exposure to determine the efficacy of antiMUC1-SOD/CAT-NPs.
TO VETERANS HEALTH) Respiratory illnesses affect over two-thirds of veterans deployed to Iraq or Afghanistan and are among the most common medical conditions in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans. Unique exposures to particulate matter in tobacco smoke and diesel exhaust particles from military vehicles likely contribute to this unusually high incidence and cause oxidative inflammation in the airway. Our strategic objective is to develop a topical medication, which could be used as a therapeutic measure against free radical pro-inflammatory action on respiratory epithelium that can persist even after removal of these environmental exposures. Our central hypothesis is that increased epithelial contact of nanoparticles conjugated with antibodies to the mucin 1 protein expressed on respiratory mucosa and with therapeutic antioxidants, superoxide and catalase, can prevent damage seen secondary to smoke and DEP exposures.
|Mulligan, Jennifer K; O'Connell, Brendan P; Pasquini, Whitney et al. (2017) Impact of tobacco smoke on upper airway dendritic cell accumulation and regulation by sinonasal epithelial cells. Int Forum Allergy Rhinol 7:777-785|