? Inhaled live biotherapeutic products show promise in addressing common pathways of disease progression that in the future can be targeted at a variety of lung diseases ,? Lal said . ? Preclinical animal data is suggestive , and safety of the potential drug in humans will be tested in a forthcoming clinical trial . Human adult safety data in COPD will help de-risk the pathway to approval for use of the drug in bronchopulmonary disease infants .
The UAB researchers hypothesized that mouse models of BPD would show heightened levels of acetylated proline-glycine-proline , or Ac-PGP , an extracellular matrix-derived peptide , as had been seen in premature infants with BPD .
This was demonstrated in BPD mouse models , and gain- or loss-of-function studies showed the impact of Ac-PGP . Intranasal instillation of Ac-PGP increased neutrophilic inflammation and lung degradation . When an inhibitor of Ac-PGP was given with the Ac-PGP , markers of neutrophilic inflammation decreased and lung structure improved .
Researchers then showed that a proprietary Lactobacilli blend of L . planatarum , L . acidophilus and L . rhamnosus performed best in synergy to reduce the inflammatory proteinase MMP-9 , which helps release the Ac-PGP from extracellular matrix . Furthermore , supernatant from Lactobacilli growth medium also reduced MMP-9 at a similar magnitude as live Lactobacilli bacteria .
A key finding was that L (+) lactic acid , which is produced in Lactobacilli growth medium supernatant , reduced MMP-9 in vitro , showing an important role for this lactic acid as an anti-inflammatory molecule . Researchers found that live Lactobacilli in the lungs provided an ongoing , sustained release of L (+) lactic acid in a controlled and well-tolerated manner .
A major technological advance reported in the study was creating the inhaled Lactobacilli powder through particle engineering ? particles small enough to reach deep into the lungs while preserving viable bacteria . This live biotherapeutic product was then tested in the BPD and COPD models . In the COPD mouse models , the blend successfully reduced inflammation in the lung microenvironment whether treated concurrently or post-injury , showing anti-inflammatory effects , decrease of several pro-inflammatory markers and elevation of the anti-inflammatory marker IgA .
An interesting finding was the favorable performance of the live biotherapeutic product . It reduced MMP-9 and other pro-inflammatory cytokines as well as , or in some cases better than , fluticasone furoate , a United States Food and Drug Administration-approved inhaled corticosteroid found in COPD combination therapies .
Safety and biodistribution studies in one of the COPD mouse models showed that inhalation of the bacterial powder did not initiate adverse reactions or disease , and the Lactobacilli did not translocate to distal tissues or accumulate in the lungs .
Co-first authors of the study , ? A Lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation ,? are Teodora Nicola and Nancy Wenger , UAB Department of Pediatrics , Division of Neonatology .
Other authors , along with Lal , Gaggar , Nicola and Wenger , are Xin Xu , Camilla Margaroli , Kristopher Genschmer , J . Edwin Blalock , UAB Department of Medicine , Division of Pulmonary , Allergy and Critical Care Medicine ; and Michael Evans , Luhua Qiao , Gabriel Rezonzew , Youfeng Yang , Tamas Jilling , Kent Willis and Namasivayam Ambalavanan , UAB Department of Pediatrics , Division of Neonatology .
Support came from National Heart , Lung and Blood Institute of the National Institutes of Health grants HL141652 , HL135710 , HL166433 , HL156275 and HL164156 .
Part of this research is patented under ? Inhaled respiratory probiotics for lung diseases of infancy , childhood and adulthood ,? U . S . 11,141,443 B2 , held under the University of Alabama at Birmingham Research Foundation , which is part of the Bill L . Harbert Institute for Innovation and Entrepreneurship , with Lal , Gaggar and Ambalavanan as inventors . This proprietary product has been commercialized through UAB startup Alveolus Bio , Inc ., based in Birmingham , Alabama , and Boston , Massachusetts .
PULMONARY , ALLERGY , AND CRITICAL CARE MEDICINE