Article

Surfactant protein D protects against acute hyperoxic lung injury.

Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4539, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 11.99). 10/2008; 178(8):805-13. DOI: 10.1164/rccm.200804-582OC
Source: PubMed

ABSTRACT 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.
To test the hypothesis that SP-D would protect against acute lung injury from hyperoxia in vivo.
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.
Compared with littermate control mice (wild-type [WT]), SP-D OE mice exposed to 80% O(2) 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-alpha, 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% O(2) demonstrated increased mortality upon withdrawal of doxycycline.
Local expression of SP-D protects against hyperoxic lung injury through modulation of proinflammatory cytokines and antioxidant enzymatic scavenger systems.

Download full-text

Full-text

Available from: Elena N Atochina-Vasserman, Jul 06, 2015
0 Followers
 · 
86 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Surfactant protein D (SP-D) is a member of the family of proteins termed collagen-like lectins or "collectins" that play a role in non-antibody-mediated innate immune responses [1]. The primary function of SP-D is the modulation of host defense and inflammation [2]. This review will discuss recent findings on the physiological importance of SP-D S-nitrosylation in biological systems and potential mechanisms that govern SP-D mediated signaling. SP-D appears to have both pro- and anti-inflammatory signaling functions. SP-D multimerization is a critical feature of its function and plays an important role in efficient innate host defense. Under baseline conditions, SP-D forms a multimer in which the N-termini are hidden in the center and the C-termini are on the surface. This multimeric form of SP-D is limited in its ability to activate inflammation. However, NO can modify key cysteine residues in the hydrophobic tail domain of SP-D resulting in a dissociation of SP-D multimers into trimers, exposing the S-nitrosylated N-termini. The exposed S-nitrosylated tail domain binds to the calreticulin/CD91 receptor complex and initiates a pro-inflammatory response through phosphorylation of p38 and NF-κB activation [3,4]. In addition, the disassembled SP-D loses its ability to block TLR4, which also results in activation of NF-κB. Recent studies have highlighted the capability of NO to modify SP-D through S-nitrosylation, causing the activation of a pro-inflammatory role for SP-D [3]. This represents a novel mechanism both for the regulation of SP-D function and NO's role in innate immunity, but also demonstrates that the S-nitrosylation can control protein function by regulating quaternary structure. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation.
    Biochimica et Biophysica Acta 12/2011; 1820(6):763-9. DOI:10.1016/j.bbagen.2011.12.006 · 4.66 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased oxidative stress is associated with perinatal asphyxia and respiratory distress in the newborn period. Induction of nuclear factor erythroid 2 p45-related factor (Nrf2) has been shown to decrease oxidative stress through the regulation of specific gene pathways. We hypothesized that Nrf2 attenuates mortality and alveolar growth inhibition in newborn mice exposed to hyperoxia. Nrf2(+/+) and Nrf2(-/-) newborn mice were exposed to hyperoxia at 24 h. Survival was significantly less in Nrf2(-/-) mice exposed to 72 h of hyperoxia and returned to room air (P < 0.0001) and in Nrf2(-/-) mice exposed to hyperoxia for 8 continuous days (P < 0.005). To determine the response of Nrf2 target genes to hyperoxia, glutathione peroxidase 2 (Gpx2) and NAD(P)H:quinone oxidoreductase (NQO1) expression was measured from lung of newborn mice using real-time PCR. In the Nrf2(+/+) mice, significant induction of lung Gpx2 and NQO1 above room air controls was found with hyperoxia. In contrast, Nrf2(-/-) mice had minimal induction of lung Gpx2 and NQO1 with hyperoxia. Expression of p21 and IL-6, genes not regulated by Nrf2, were also measured. IL-6 expression in Nrf2(-/-) lung was markedly induced by 72 h of hyperoxia in contrast to the Nrf2(+/+) mice. p21 was induced in both Nrf2(+/+) and Nrf2(-/-) lung by hyperoxia. Mean linear intercept (MLI) and mean chord length (MCL) were significantly increased in 14-day-old Nrf2(-/-) mice previously exposed to hyperoxia compared with Nrf2(+/+) mice. The percentage of surfactant protein C (Sp-c(+)) type 2 alveolar cells in 14-day-old Nrf2(-/-) mice exposed to neonatal hyperoxia was also significantly less than Nrf2(+/+) mice (P < 0.02). In summary, these findings indicate that Nrf2 increases survival in newborn mice exposed to hyperoxia and that Nrf2 may help attenuate alveolar growth inhibition caused by hyperoxia exposure.
    AJP Lung Cellular and Molecular Physiology 04/2009; 296(4):L565-73. DOI:10.1152/ajplung.90487.2008 · 4.04 Impact Factor