title: Recombinant adenoviral vector disrupts surfactant homeostasis in mouse lung.
abstract: Although replication-deficient adenoviruses efficiently transfer genes into epithelial cells of the lung, host immune responses limit the extent and duration of gene expression. To define further the role of inflammatory responses to first-generation, recombinant, deltaE1, deltaE3 adenovirus in lung pathology and surfactant protein homeostasis, expression of the surfactant proteins SP-A, SP-B, and proSP-C was determined by immunohistochemistry 2, 7, and 14 days following intratracheal administration of 2 x 10(9) pfu of a recombinant adenovirus, Av1Luc1, to BALB/c nu/nu and BALB/c wild-type mice. Two to 7 days after virus administration, an acute inflammatory response was observed in both mouse strains. Respiratory epithelial cells were sloughed, and extracellular accumulation of SP-A and SP-B was detected in the airways. Diminished immunostaining for SP-A and SP-B was noted in type II cells, and SP-A and SP-B mRNA expression was decreased in focal regions of the lungs from both mouse strains. One week after virus administration, immunostaining for proSP-C was markedly increased in cells lining the regenerating alveolar epithelial surfaces. Two weeks after Av1Luc1 treatment of nu/nu mice, immunostaining for SP-A, SP-B, and proSP-C was similar to those patterns observed prior to adenoviral administration. In immunocompetent wild-type mice, however, immunostaining for surfactant proteins was absent in areas associated with chronic lymphocytic infiltration. The recombinant adenoviral vector, Av1Luc1, caused acute inflammatory responses in the respiratory epithelium with disruption of surfactant protein homeostasis in both wild-type and nu/nu mice. Alterations in surfactant homeostasis persisted in wild-type mice. Thus, both acute and thymic-dependent immune responses limit transgene expression and disrupt surfactant protein gene expression and homeostasis. Because surfactant proteins are critical to host defense and to the maintenance of alveolar stability following injury, these findings raise concerns regarding both acute and chronic toxicity of first-generation recombinant adenoviral vectors for gene transfer.
authors.affiliation: Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, OH 45229-3039, USA.
authors.forename: Z K
authors.initials: ZK
authors.lastname: Zsengellér
authors.forename: S E
authors.initials: SE
authors.lastname: Wert
authors.forename: C J
authors.initials: CJ
authors.lastname: Bachurski
authors.forename: K L
authors.initials: KL
authors.lastname: Kirwin
authors.forename: B C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: J A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000256:Adenoviridae; D000257:Adenoviridae Infections / Q000150:complications / Q000378:metabolism*; D000818:Animals; D005822:Genetic Vectors / Q000009:adverse effects / Q000494:pharmacology; D006706:Homeostasis; D007249:Inflammation / Q000503:physiopathology; D008168:Lung / Q000502:physiology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger