Safety, tolerability, and biomarkers of the treatment of mice with aerosolized toll-like receptor ligands

We have previously discovered a synergistically therapeutic combination of two Toll-like receptor (TLR) ligands, an oligodeoxynucleotide (ODN) and Pam2CSK4. Aerosolization of these ligands stimulates innate immunity within the lungs to prevent pneumonia from bacterial and viral pathogens. Here we ex...

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Main Authors: Victoria eAlfaro (Author), David L. Goldblatt (Author), Gabriella R. Valverde (Author), Mark eMunsell (Author), Lee J. Quinton (Author), Adam K. Walker (Author), Robert eDantzer (Author), Atul eVaradhachary (Author), Brenton L. Scott (Author), Scott E. Evans (Author), Michael J. Tuvim (Author), Burton F Dickey (Author)
Format: Book
Published: Frontiers Media S.A., 2014-02-01T00:00:00Z.
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100 1 0 |a Victoria eAlfaro  |e author 
700 1 0 |a David L. Goldblatt  |e author 
700 1 0 |a Gabriella R. Valverde  |e author 
700 1 0 |a Mark eMunsell  |e author 
700 1 0 |a Lee J. Quinton  |e author 
700 1 0 |a Adam K. Walker  |e author 
700 1 0 |a Robert eDantzer  |e author 
700 1 0 |a Atul eVaradhachary  |e author 
700 1 0 |a Brenton L. Scott  |e author 
700 1 0 |a Scott E. Evans  |e author 
700 1 0 |a Michael J. Tuvim  |e author 
700 1 0 |a Burton F Dickey  |e author 
245 0 0 |a Safety, tolerability, and biomarkers of the treatment of mice with aerosolized toll-like receptor ligands 
260 |b Frontiers Media S.A.,   |c 2014-02-01T00:00:00Z. 
500 |a 1663-9812 
500 |a 10.3389/fphar.2014.00008 
520 |a We have previously discovered a synergistically therapeutic combination of two Toll-like receptor (TLR) ligands, an oligodeoxynucleotide (ODN) and Pam2CSK4. Aerosolization of these ligands stimulates innate immunity within the lungs to prevent pneumonia from bacterial and viral pathogens. Here we examined the safety and tolerability of this treatment in mice, and characterized the expression of biomarkers of innate immune activation. We found that neutrophils appeared in lung lavage fluid 4 hours after treatment, reached a peak at 48 hours, and resolved by 7 days. The peak of neutrophil influx was accompanied by a small increase in lung permeability. Despite the abundance of neutrophils in lung lavage fluid, only rare neutrophils were visible histopathologically in the interstitium surrounding bronchi and veins and none were visible in alveolar airspaces. The cytokines IL-6, TNF and CXCL2 rose several hundred-fold in lung lavage fluid 4 hours after treatment in a dose-dependent and synergistic manner, providing useful biomarkers of lung activation. IL-6 rose five-fold in serum with delayed kinetics compared to its rise in lavage fluid, and might serve as a systemic biomarker of immune activation of the lungs. The dose-response relationship of lavage fluid cytokines was preserved in mice that underwent myeloablative treatment with cytosine arabinoside to model the treatment of hematologic malignancy. There were no overt signs of distress in mice treated with ODN/Pam2CSK4 in doses up to 8-fold the therapeutic dose, and no changes in temperature, respiratory rate, or behavioral signs of sickness including sugar water preference, food disappearance, cage exploration or social interaction, though there was a small degree of transient weight loss. We conclude that treatment with aerosolized ODN/Pam2CSK4 is well tolerated in mice, and that innate immune activation of the lungs can be monitored by the measurement of inflammatory cytokines in lung lavage fluid and serum. 
546 |a EN 
690 |a Pneumonia 
690 |a innate immunity 
690 |a Toll-like receptor 
690 |a aerosol 
690 |a lipopeptide 
690 |a oligodeoxynucleotide 
690 |a Therapeutics. Pharmacology 
690 |a RM1-950 
655 7 |a article  |2 local 
786 0 |n Frontiers in Pharmacology, Vol 5 (2014) 
787 0 |n http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00008/full 
787 0 |n https://doaj.org/toc/1663-9812 
856 4 1 |u https://doaj.org/article/a9c99de398994a0b8e8210007dbd1b7c  |z Connect to this object online.