title: Eosinophilic inclusions in rat Clara cells and the effect of an inhaled corticosteroid.
abstract: Large eosinophilic cytoplasmic inclusions (ECIs) are occasionally seen in untreated rat Clara cells. Following inhalation exposure to a corticosteroid, the number of ECIs was increased. This is the first histopathological description of rat ECIs and attempted characterization by immunohistochemistry, in situ hybridization, and electron microscopy. ECIs were strongly positive for surfactant protein D (SP-D) and weakly positive for Clara cell specific protein (CCSP). Clara cell cytoplasm was positive for CCSP mRNA regardless of ECIs, but not within ECIs. Corticosteroid treatment and ECI presence did not affect the immunohistochemistry and in situ hybridization staining intensities. Electron microscopy revealed large intracytoplasmic granules with an irregular limiting membrane. The ECI number was microscopically quantified in rats from three-, six-, and twenty-four-month studies. The mean ECI counts in treated rats increased from three- to fifty-four-fold with a positive dose-related trend, when compared with vehicle controls. Although the mechanism is unclear, SP-D and to a lesser extent CCSP accumulate in the ECIs. As human bronchial epithelium does not appear to contain structures analogous to the ECI, it is suggested that the observation of an increased number of ECIs in the treated rats is not likely to be relevant for human clinical risk assessment.
authors.affiliation: Pathology, Safety Assessment-UK, GlaxoSmithKline, Ware, UK. takahito.x.kambara@gsk.com
authors.forename: Takahito
authors.initials: T
authors.lastname: Kambara
authors.forename: Tom P
authors.initials: TP
authors.lastname: McKevitt
authors.forename: Ian
authors.initials: I
authors.lastname: Francis
authors.forename: Jennie A
authors.initials: JA
authors.lastname: Woodfine
authors.forename: Sean J
authors.initials: SJ
authors.lastname: McCawley
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Jones
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Pilling
authors.forename: David J
authors.initials: DJ
authors.lastname: Lewis
authors.forename: Tom C
authors.initials: TC
authors.lastname: Williams
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000378:metabolism / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D002479:Inclusion Bodies / Q000378:metabolism* / Q000648:ultrastructure; D019570:Inhalation Exposure / Q000009:adverse effects*; D008297:Male; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000305:Adrenal Cortex Hormones; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; C556389:SCGB1A1 protein, human; C556391:Scgb1a1 protein, rat; D014598:Uteroglobin