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Surfactant Protein D Protects against Acute Hyperoxic Lung Injury

¹ Surfactant Biology Laboratories, Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Michael F. Beers, M.D., Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, SVM Hill Pavilion Room H410F, 380 S. University Avenue, Philadelphia, PA 19104-4539. E-mail: mfbeers{at}mail.med.upenn.edu

Rationale: Surfactant protein D (SP-D) is a member of the collectin family of soluble, innate, host defense molecules with demonstrated immunomodulatory properties in vitro. Constitutive absence of SP-D in mice is associated with lung inflammation, alteration in surfactant lipid homeostasis, and increased oxidative-nitrative stress.

Objectives: To test the hypothesis that SP-D would protect against acute lung injury from hyperoxia in vivo.

Methods: Transgenic mice overexpressing rat SP-D constitutively (SP-D OE) or conditionally via regulation with doxycycline (SP-D Dox-on) were subjected to continuous hyperoxic challenge for up to 14 days.

Measurements and Main Results: Compared with littermate control mice (wild-type [WT]), SP-D OE mice exposed to 80% O₂ demonstrated substantially increased survival accompanied by significant reductions in wet to dry lung ratios and bronchoalveolar lavage (BAL) protein. Although SP-D OE and WT mice exhibited a twofold increase in total BAL cells and neutrophilia in response to hyperoxia, the SP-D OE group had lower levels of BAL proinflammatory cytokines and chemokines, including IL-6, tumor necrosis factor-, and monocyte chemotactic protein-1; increased mRNA levels of the transcription factor NF-E2 related factor-2 (NRF-2) and phase 2 antioxidants hemoxygenase-1 (HO-1), glutathione peroxidase-2 (GPx-2) and NAD(P)H quinone oxidoreductase-1 (Nqo-1); and decreases in lung tissue thiobarbituric acid–reactive substances. As proof of principle, the protective role of SP-D on hyperoxic injury was confirmed as SP-D Dox-on mice exposed to 85% O₂ demonstrated increased mortality upon withdrawal of doxycycline.

Conclusions: Local expression of SP-D protects against hyperoxic lung injury through modulation of proinflammatory cytokines and antioxidant enzymatic scavenger systems.

Key Words: innate immunity • inflammation • collectin • antioxidants • oxidative stress

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Surfactant protein D (SP-D), a pulmonary collectin with important immunomodulatory properties, is up-regulated in response to various inflammatory and infectious stimuli. The role of SP-D in modulating inflammatory events in acute lung injury is undefined. What This Study Adds to the Field These results provide in vivo evidence for an antiinflammatory effect of SP-D in response to noninfectious acute lung injury and suggest a potential new therapeutic role for SP-D against hyperoxic lung injury.