The use of an endothelium-targeted cationic copolymer to enhance the barrier function of lung capillary endothelial monolayers.
Acute changes in lung capillary permeability continue to complicate procedures such as cardiopulmonary bypass, solid organ transplant, and major vascular surgery and precipitate the more severe disease state Adult Respiratory Distress Syndrome (ARDS). To date there is no treatment targeted directly to the lung microvasculature. We hypothesized that biomimetic polymers could be used to enhance passive barrier function by reducing the porosity of the endothelial glycocalyx and attenuate mechanotransduction by restricting the motion of the glycoproteins implicated in signal transduction. To this end, cationic copolymers containing methacrylamidopropyl trimethylammonium chloride (P-TMA Cl) have been developed as an infusible therapy to target the lung capillary glycocalyx in order to mechanically enhance the capillary barrier and turn off pressure-induced mechanotransduction. Copolymers were tested for functional efficacy by measuring both albumin permeability (P(DA)) and hydraulic conductivity (L(p)) across cultured endothelial monolayers. P-TMA Cl significantly decreased P(DA) in normal and inflamed cells and attenuated pressure-induced increases in L(p). Decreases in L(p) across endothelial monolayers in the presence of P-TMA Cl is evidence of a dampening of mechanotransduction-induced barrier dysfunction. We show the potential for biomimetic polymers targeted to lung endothelium as a viable therapy to enhance endothelial barrier function thereby attenuating a major component of vascular inflammation.
Giantsos
Kristina M
KM
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Kopeckova
Pavla
P
Dull
Randal O
RO
D000643:Ammonium Chloride / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D002196:Capillaries / Q000187:drug effects* / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002412:Cations; D002417:Cattle; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D008689:Methacrylates / Q000008:administration & dosage* / Q000737:chemistry
D002412:Cations; D008689:Methacrylates; D000643:Ammonium Chloride; C400723:MAPTAC