Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection

Glasser, Stephan W.; Witt, Teah L.; Senft, Albert P.; Baatz, John E.; Folger, Dusti; Maxfield, Melissa D.; Akinbi, Henry T.; Newton, Danforth A.; Prows, Daniel R.; Korfhagen, Thomas R.

doi:10.1152/ajplung.90640.2008

Cited by 80 publications

(78 citation statements)

References 36 publications

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“…SP-C was shown to block dsRNA stimulation of TLR3 signaling in vitro suggesting that SP-C may modulate early events in viral infection including receptor activity. 33 The infection susceptibility of SP-C-defi cient mice and infection-related exacerbation in humans is consistent with the emerging view that SP-C is an essential component of pulmonary innate host defense.…”

Section: Neuroendocrine Cells and Diffuse Lung Diseasesupporting

confidence: 79%

Pathogenesis of Interstitial Lung Disease in Children and Adults

Glasser¹,

Hardie²,

Hagood³

2010

Pediatric Allergy, Immunology, and Pulmonology

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Interstitial lung diseases (ILDs) occur across the lifespan, from birth to advanced age. However, the causes, clinical manifestations, histopathology, and management of ILD differ greatly among infants, older children, and adults. The historical approach of classifying childhood ILD (chILD) using adult classifi cation schemes may therefore have done more harm than good. Nevertheless, identifi cation of novel forms of chILD in the past decade, such as surfactant metabolism dysfunction disorders and neuroendocrine cell hyperplasia of infancy (NEHI), as well as genomic analysis of adult ILDs, has taught us that identical genotypes may result in distinct phenotypes at different ages and developmental stages, and that lung developmental pathways and cellular phenotypes are often recapitulated in adult ILDs. Thus comparison of the pathophysiology of ILD in children and adults in the context of lung development is useful in understanding the pathogenesis of these disorders, and may lead to novel therapeutic interventions for ILDs at all ages.

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Section: Neuroendocrine Cells and Diffuse Lung Diseasesupporting

confidence: 79%

Pathogenesis of Interstitial Lung Disease in Children and Adults

Glasser¹,

Hardie²,

Hagood³

2010

Pediatric Allergy, Immunology, and Pulmonology

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“…Thus, although SP-A and SP-D and minor surfactant phospholipid species influence LPSinduced inflammation, the current findings are consistent with an essential role for SP-C in protection from repetitive LPS injury. Sftpc 2/2 mice were found to be more susceptible to infection with the respiratory pathogen, RSV (13). RSV induces inflammation by double-stranded RNA activation through the TLR family member, TLR3.…”

Section: Discussionmentioning

confidence: 99%

“…LPS was delivered by noninvasive oral aspiration, as described previously (13). Briefly, mice were lightly anesthetized and suspended by upper incisors on a 45 8 -angle incline board.…”

Section: In Vivo Model Of Recurrent Lps Exposurementioning

confidence: 99%

“…SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with respiratory syncytial virus (RSV) and Pseudomonas aeruginosa, and showed a more robust inflammatory reaction compared with strain-matched wild-type Sftpc 1/1 mice (12,13). The patient and mouse model data show that SP-C is an innate immune molecule providing both antimicrobial and anti-inflammatory function in the lung.…”

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confidence: 99%

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Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

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Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc 2/2 ) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc 1/1 and Sftpc 2/2 mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc 2/2 mice at 3 and 5 days after the final dose. Compared with Sftpc 1/1 mice, inflammatory injury persisted in the lungs of Sftpc 2/2 mice 30 days after the final LPS challenge. Sftpc 2/2 mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc 2/2 type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc 1/1 cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.Keywords: surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4Surfactant protein-C (SP-C) is an abundant 3.5-kD surfactantassociated protein expressed and secreted by alveolar type II epithelial cells. The mature airspace form of SP-C is highly hydrophobic and palmitoylated at adjacent amino terminal cysteine residues (1). Mutations in the gene encoding human SP-C (SFTPC) have been shown to cause familial interstitial lung disease (ILD). Affected individuals express an altered proSP-C, leading to reduced levels of mature SP-C in the airspace (2-4). SP-C deficiencies without detectable mutations in the protein-coding region of SFTPC or due to promoter mutations have also been reported, and represent a true null condition (5-7). These individuals also develop ILD, including idiopathic pulmonary fibrosis (IPF). SP-C deficiency-related disease may arise as an acute childhood or as a late-onset disease in adulthood (3). Because SP-C is expressed exclusively in alveolar type II cells, the associated ILD/idiopathic pulmonary fibrosis presumably originates from a primary defect in the epithelium. SP-C deficiency increases susceptibility to viral-or bacterial-induced exacerbations in affected children (5,6,(8)(9)(10). SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with ...

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“…Both downregulated genes (Idfb3 and Tlr3) were previously indentified to be involved in pathogenesis of ALI and acute respiratory distress syndrome (13,61). Moreover, Tlr3 has also been shown to be altered in surfactant protein C-deficient mice (28). Recently, it has been reported that Ctgf and Cyr61 are early responding genes of VILI (70).…”

Section: Conventional Interface Experiments Seementioning

confidence: 99%

Interfacial stress affects rat alveolar type II cell signaling and gene expression

Hobi

Ravasio

Haller

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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.) showed that contact of alveolar epithelial type II cells with an air-liquid interface (I AL) leads to a paradoxical situation. It is a potential threat that can cause cell injury, but also a Ca 2ϩ -dependent stimulus for surfactant secretion. Both events can be explained by the impact of interfacial tensile forces on cellular structures. Here, the strength of this mechanical stimulus became also apparent in microarray studies by a rapid and significant change on the transcriptional level. Cells challenged with an IAL in two different ways showed activation/inactivation of cellular pathways involved in stress response and defense, and a detailed Pubmatrix search identified genes associated with several lung diseases and injuries. Altogether, they suggest a close relationship of interfacial stress sensation with current models in alveolar micromechanics. Further similarities between IAL and cell stretch were found with respect to the underlying signaling events. The source of Ca 2ϩ was extracellular, and the transmembrane Ca 2ϩ entry pathway suggests the involvement of a mechanosensitive channel. We conclude that alveolar type II cells, due to their location and morphology, are specific sensors of the IAL, but largely protected from interfacial stress by surfactant release. cell deformation; cell injury; mechanotransduction; microarray; stretch IN THE ALVEOLI, MECHANICAL forces are a constant modulator of tissue geometry and function (4). These forces arise from multiple sources, such as cyclic stretching and compression during respiration, changes in transcapillary pressure, or surface tension at the air-liquid interface (I AL ) (22). They are probably nonuniform in space and time (26,51,67) and impose either physiological responses of the cells, or pathological ones, depending on the type of tissue or the magnitude or abnormality of forces that are at work (reviewed in Refs. 18,66,69,72). In particular, tissue stretch (ϭ tensile strain) has already been shown to be an important determinant of surfactant secretion in alveolar type II (AT II) cells (2,15,36,47,71,73). Studies on single cells revealed that stretch induces an elevation of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (23, 73), perhaps via mechanosensitive ion channels like the wellcharacterized transient receptor potential (TRP) vanilloids (reviewed in Refs. 16,77). Recently, the panoply of mechanosensitive mechanisms was expanded by the finding that the I AL , the "normal" microenvironment of the AT II cells (6), may be a strong mechanical incentive as well. Two recent independent studies (55, 56) described a stimulating, but also harmful, effect of an I AL on the AT II cell function. Interestingly, interfacial contact is followed by an increase in [Ca 2ϩ ] i and release of ATP, both of which stimulate secretion (reviewed in Refs. 1, 44, 59). It has even been speculated that this response could act within a feedback loop to continuously monitor and to adjust the physical properties of the interface or the hypophase below.In addition...

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Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection

Cited by 80 publications

References 36 publications

Pathogenesis of Interstitial Lung Disease in Children and Adults

Pathogenesis of Interstitial Lung Disease in Children and Adults

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Interfacial stress affects rat alveolar type II cell signaling and gene expression

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