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SP-D-deficient mice are resistant to hyperoxia

¹Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ²Department of Pharmacology, Rutgers University, Piscataway, New Jersey; and ³Department of Pediatrics, University of Texas Southwestern at Dallas, Dallas, Texas

Submitted 14 April 2006 ; accepted in final form 30 November 2006

Surfactant protein D (SP-D), a member of the collectin superfamily, modulates pulmonary inflammatory responses and innate immunity. Disruption of the SP-D gene in mice induces peribronchiolar inflammation, accumulation of large, foamy macrophages, increased bronchoalveolar lavage (BAL) phospholipid, and pulmonary emphysema. We hypothesized that absence of SP-D aggravates hyperoxia-induced injury. To test this, SP-D-deficient (SP-D^–/–) and wild-type (SP-D^+/+) mice were exposed to 80% or 21% oxygen. Paradoxically, during 14 days of hyperoxia, SP-D^–/– mice had 100% survival vs. 30% in SP-D^+/+. The survival advantage in SP-D^–/– mice was accompanied by lower histopathological injury scores at days 5 and 14, although total BAL cells (8.2 ± 1.4 x 10⁵ in SP-D^–/– vs. 4.04 ± 0.25 x 10⁵ in SP-D^+/+ mice) and neutrophils (1.2 ± 0.4 x 10⁵ vs. 0.03 ± 0.02 x 10⁵ in SP-D^–/– and SP-D^+/+, respectively) were increased. In addition, BAL protein and lung-to-body weight ratios were similarly elevated in both groups after 3, 5, and 14 days of continuous exposure. Biochemically, in contrast to SP-D^+/+, SP-D^–/– mice had higher levels of surfactant phospholipid and SP-B at baseline and 5 days after hyperoxia accompanied by a preservation of surfactant biophysical activity. From a multiplex assay of nine cytokines, we found elevated levels of IL-13 in BAL fluid of normoxic SP-D^–/– mice compared with SP-D^+/+. We conclude that the resistance of SP-D-deficient mice to hyperoxia reflects homeostatic changes in the SP-D^–/– phenotype involving both phospholipid and SP-B-mediated induced resistance of surfactant to inactivation as well as changes in the immunomodulatory BAL cytokine profile.

surfactant protein D; inflammation; alveolar macrophages; collectin

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