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1 Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States
2 Philadelphia, Pennsylvania, United States; Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States
3 Philadelphia, Pennsylvania, United States; Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
4 Pediatrics, University of Texas-Southwestern, Dallas, Texas, United States
5 Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: mfbeers{at}mail.med.upenn.edu.
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 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 versus 30% in SP-D+/+. The survival advantage in SP-D-/- mice was accompanied by lower histopathologic injury scores at days 5 and 14, although total BAL cells (8.2 ± 1.4 *105 in SP-D-/- vs. 4.04 ± 0.25 *105 in SP-D+/+ mice), and neutrophils (1.2 ± 0.4 *105 vs. 0.03 ± 0.02 *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 as compared to SP-D+/+. We conclude that the resistance of SP-D deficient mice to hyperoxia reflects homeostatic changes in the SP-D-/- phenotype involving phospholipid and SP-B mediated resistance of surfactant to inactivation as well as changes the immunomodulatory BAL cytokine profile.
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