title: Cholesterol-mediated surfactant dysfunction is mitigated by surfactant protein A.
abstract: The ability of pulmonary surfactant to reduce surface tension at the alveolar surface is impaired in various lung diseases. Recent animal studies indicate that elevated levels of cholesterol within surfactant may contribute to its inhibition. It was hypothesized that elevated cholesterol levels within surfactant inhibit human surfactant biophysical function and that these effects can be reversed by surfactant protein A (SP-A). The initial experiment examined the function of surfactant from mechanically ventilated trauma patients in the presence and absence of a cholesterol sequestering agent, methyl-β-cyclodextrin. The results demonstrated improved surface activity when cholesterol was sequestered in vitro using a captive bubble surfactometer (CBS). These results were explored further by reconstitution of surfactant with various concentrations of cholesterol with and without SP-A, and testing of the functionality of these samples in vitro with the CBS and in vivo using surfactant depleted rats. Overall, the results consistently demonstrated that surfactant function was inhibited by levels of cholesterol of 10% (w/w phospholipid) but this inhibition was mitigated by the presence of SP-A. It is concluded that cholesterol-induced surfactant inhibition can actively contribute to physiological impairment of the lungs in mechanically ventilated patients and that SP-A levels may be important to maintain surfactant function in the presence of high cholesterol within surfactant.
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada. Electronic address: jquahian@gmail.com.
authors.forename: Joshua Qua
authors.initials: JQ
authors.lastname: Hiansen
authors.affiliation: Lawson Health Research Institute, London, Ontario, Canada. Electronic address: ekeatin2@uwo.ca.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Keating
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada. Electronic address: aaspros@gmail.com.
authors.forename: Alex
authors.initials: A
authors.lastname: Aspros
authors.affiliation: Lawson Health Research Institute, London, Ontario, Canada. Electronic address: jyao@uwo.ca.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Yao
authors.affiliation: Department of Medicine, The University of Western Ontario, London, Ontario, Canada. Electronic address: kbosma2@uwo.ca.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Bosma
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada; Department of Medicine, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: cyamash@uwo.ca.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Yamashita
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada; Department of Medicine, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: jflewis@uwo.ca.
authors.forename: James F
authors.initials: JF
authors.lastname: Lewis
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada; Department of Medicine, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: rveldhui@uwo.ca.
authors.forename: Ruud A W
authors.initials: RA
authors.lastname: Veldhuizen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017563:Lung Diseases, Interstitial / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D010743:Phospholipids / Q000378:metabolism / Q000494:pharmacology; D011312:Pressure; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism* / Q000494:pharmacology; D011663:Pulmonary Surfactants / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012121:Respiration, Artificial / Q000379:methods*; D013500:Surface Tension / Q000187:drug effects; D055815:Young Adult; D047392:beta-Cyclodextrins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D010743:Phospholipids; D037662:Pulmonary Surfactant-Associated Protein A; D011663:Pulmonary Surfactants; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D010100:Oxygen
keywords: Cholesterol; Mechanical ventilation; Pulmonary surfactant; SP-A