Delayed Clearance of<i>Pneumocystis carinii</i>Infection, Increased Inflammation, and Altered Nitric Oxide Metabolism in Lungs of Surfactant Protein–D Knockout Mice

Atochina, Elena N.; Gow, Andrew J.; Beck, James M.; Haczku, Angela Franciska; Inch, Adam; Kadire, Helchem; Tomer, Yaniv; Davis, Christine; Preston, Angela M.; Poulain, Francis R; Hawgood, Samuel; Beers, Michael F.

doi:10.1086/383130

Cited by 75 publications

(57 citation statements)

References 57 publications

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“…In contrast to increased susceptibility to acute lung injury induced by pathogens (6,45) and bleomycin (17), we found that exposure to 80% oxygen resulted in mortality exclusively in SP-D ϩ/ϩ . As shown in Fig.…”

Section: Sp-dcontrasting

confidence: 80%

“…In SP-D Ϫ/Ϫ mice, we showed increased susceptibility to bleomycin and evidence of oxidative-nitrative stress (17). Similar findings were observed when the same mice were infected with Pneumocystis carinii (6). Based on the anti-inflammatory properties of SP-D and its association with altered nitric oxide metabolism in both infectious and noninfectious (bleomycin) models of lung injury, we hypothesized that the inflammatory response to pure hyperoxic injury could also be exacerbated by the absence of SP-D. Paradoxically, we found that chronic SP-D deficiency confers resistance to hyperoxia-mediated lung injury.…”

supporting

confidence: 81%

“…8). (3,6,45,46) as well as to noninfectious bleomycin-induced lung injury (17) has been previously reported. Protection of surfactant phospholipids and macrophages from oxidative damage in vitro by direct antioxidant functions of SP-D has also been observed (16).…”

Section: Sp-dmentioning

confidence: 92%

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SP-D-deficient mice are resistant to hyperoxia

Jain¹,

Atochina‐Vasserman²,

Kadire³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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surfactant protein D; inflammation; alveolar macrophages; collectin AS A BYPRODUCT OF THE USE of high oxygen (O 2 ) concentrations often required in management of patients with respiratory failure, reactive oxygen species produced during hyperoxic exposure can adversely affect the lung. It has been proposed that the balance between oxygen radical production and antioxidant capacities can modulate oxygen-mediated injury. The lung responds to hyperoxia by enhancing the expression of cytoprotective proteins including antioxidants (65), DNA repair enzymes (55), and regulators of cell survival. In addition, elevated expression of certain surfactant components occurs in lungs of adult (54) and neonatal rats (64) during adaptation to both sublethal (85%) and lethal (95%) oxygen (1).Surfactant protein D (SP-D), an airway epithelial secretory product, belongs to the superfamily of mammalian C-type (Ca 2ϩ -binding) lectins (collectins), which also includes SP-A and serum mannose-binding lectin. Like all collectins, monomeric SP-D is distinguished by the presence of an NH 2 -terminal cysteine-rich domain, a collagen domain, a coiled-coil neck domain, and a lectin domain with calcium-dependent regulatory elements. SP-D monomers associate through their collagenous domains to form a basic functional trimer, which then associates into higher order multimers. This oligomeric assembly provides high avidity, affinity, and specificity to SP-D ligand recognition. In the lung, SP-D ligands include allergens, particles, bacterial cell wall components, and viral envelope proteins (26). SP-D is also known to be chemotactic for neutrophils and mononuclear phagocytes (25) and to modulate alveolar type II (61) and macrophage function in vitro (39).SP-D is produced primarily by alveolar type II cells and nonciliated bronchiolar cells in the lung (24) and is constitutively secreted into the alveoli where it influences surfactant homeostasis (40), effector cell functions, and host defense. It is upregulated in a variety of inflammatory and infectious conditions including Pneumocystis pneumonia (5), asthma (2), and bleomycin injury (17). Mice or rats exposed to hyperoxic challenge also have increases in SP-D (13), suggesting that it may have a role in protection from this insult.Targeted disruption of the SP-D gene in vivo in two genetically different backgrounds has been shown to result in mice with increased alveolar and cellular pools of surfactant phospholipid, accelerated development of age-related emphysema, and large, foamy macrophages (14,40). These SP-D null mice (SP-D Ϫ/Ϫ ) also exhibit an increase in the baseline level of inflammation in the lung, increases in metalloproteinase activity, and biochemical evidence of enhanced oxidative-nitrative stress (4, 63). In addition, SP-D deficiency also confers susceptibility to specific bacterial (45) and viral infections (46).We have previously reported modulation of bleomycininduced lung injury by SP-D. In SP-D Ϫ/Ϫ mice, we showed increased susceptibility to bleomycin and evidence of oxida...

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Section: Sp-dcontrasting

confidence: 80%

supporting

confidence: 81%

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SP-D-deficient mice are resistant to hyperoxia

Jain¹,

Atochina‐Vasserman²,

Kadire³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This protein is a constitutive mediator of Ag clearance and is capable of interacting with cellular components of both the innate and adaptive immune systems on mucosal surfaces (1,2). SP-D is a potent inhibitor of T cell function in vitro (3)(4)(5)(6) and was shown to protect against various inflammatory responses in the lung in vivo (7)(8)(9)(10)(11)(12)(13). SP-D is synthesized and secreted primarily by type II alveolar cells, Clara cells, and cells of submucosal glands in the lung (14), but this collectin can also be found in epithelial surfaces of many other organs (14 -18).…”

mentioning

confidence: 99%

IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response

Haczku

Cao

Vass

et al. 2006

The Journal of Immunology

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127

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The innate immune molecule surfactant protein-D (SP-D) plays an important regulatory role in the allergic airway response. In this study, we demonstrate that mice sensitized and challenged with either Aspergillus fumigatus (Af) or OVA have increased SP-D levels in their lung. SP-D mRNA and protein levels in the lung also increased in response to either rIL-4 or rIL-13 treatment. Type II alveolar epithelial cell expression of IL-4Rs in mice sensitized and challenged with Af, and in vitro induction of SP-D mRNA and protein by IL-4 and IL-13, but not IFN-γ, suggested a direct role of IL-4R-mediated events. The regulatory function of IL-4 and IL-13 was further supported in STAT-6-deficient mice as well as in IL-4/IL-13 double knockout mice that failed to increase SP-D production upon allergen challenge. Interestingly, addition of rSP-D significantly inhibited Af-driven Th2 cell activation in vitro whereas mice lacking SP-D had increased numbers of CD4+ cells with elevated IL-13 and thymus- and activation-regulated chemokine levels in the lung and showed exaggerated production of IgE and IgG1 following allergic sensitization. We propose that allergen exposure induces elevation in SP-D protein levels in an IL-4/IL-13-dependent manner, which in turn, prevents further activation of sensitized T cells. This negative feedback regulatory circuit could be essential in protecting the airways from inflammatory damage after allergen inhalation.

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“…In vivo, the use of transgenic mouse models suggests a protective role for SP-D against damage by inflammatory stimuli. Local up-regulation of SP-D protein levels in wild-type mice occurs after a variety of infectious and inflammatory lung injuries, including bacterial and fungal pneumonia, bleomycin, and hyperoxia (12)(13)(14), while mice constitutively deficient in SP-D develop, at baseline, progressive lung inflammation and time-dependent airspace remodeling (15).…”

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confidence: 99%

Surfactant Protein D Protects against Acute Hyperoxic Lung Injury

Jain

Atochina‐Vasserman

Tomer

et al. 2008

Am J Respir Crit Care Med

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

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Delayed Clearance ofPneumocystis cariniiInfection, Increased Inflammation, and Altered Nitric Oxide Metabolism in Lungs of Surfactant Protein–D Knockout Mice

Cited by 75 publications

References 57 publications

SP-D-deficient mice are resistant to hyperoxia

SP-D-deficient mice are resistant to hyperoxia

IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response

Surfactant Protein D Protects against Acute Hyperoxic Lung Injury

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