Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis

Chibbar, Rajni; Shih, Francis; Båga, Monica; Torlakovic, Emina; Ramlall, Kumar; Skomro, Robert; Cockcroft, Donald W.; Lemire, Edmond G.

doi:10.1038/modpathol.3800149

Cited by 98 publications

(84 citation statements)

References 31 publications

(26 reference statements)

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“…The overexpression of mutant proSP-C can cause cytotoxicity in transfected cells (4) and transgenic mice (6). However, not all individuals who carry a diseaseassociated mutant SFTPC allele are symptomatic (4,5). This observation led to the hypothesis that misfolded proSP-C is normally rapidly degraded but, under specific conditions (e.g., viral infection), might accumulate to form cytotoxic aggregates that, in turn, could trigger disease onset (7).…”

Section: L188qmentioning

confidence: 99%

“…A number of other autosomal dominant SFTPC mutations were subsequently identified with a range of histological phenotypes, even within kindreds. For example, a mutation leading to the substitution of glutamine for leucine at position 188 of proSP-C (SP-C L188Q ) resulted in a variable disease onset, with nonspecific interstitial pneumonia (NSIP) in children and usual interstitial pneumonia (UIP) in adults of the same family (4,5).…”

Section: L188qmentioning

confidence: 99%

See 1 more Smart Citation

4-Phenylbutyric Acid Treatment Rescues Trafficking and Processing of a Mutant Surfactant Protein–C

Stewart

Ridsdale

Martin

et al. 2012

Am J Respir Cell Mol Biol

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Section: L188qmentioning

confidence: 99%

Section: L188qmentioning

confidence: 99%

4-Phenylbutyric Acid Treatment Rescues Trafficking and Processing of a Mutant Surfactant Protein–C

Stewart

Ridsdale

Martin

et al. 2012

Am J Respir Cell Mol Biol

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“…https://doi.org/10.1183/16000617.0018-2017C, respectively) have been linked with interstitial lung disease of the usual interstitial pneumonitis and nonspecific interstitial pneumonitis patterns [52][53][54][55][56][57]. When expressed in cultured cells, some of these mutant proteins trigger the UPR.…”

Section: Pulmonary Fibrosismentioning

confidence: 99%

Endoplasmic reticulum stress in lung disease

Marciniak

2017

Eur Respir Rev

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Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease.

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“…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).…”

mentioning

confidence: 99%

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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Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis

Cited by 98 publications

References 31 publications

4-Phenylbutyric Acid Treatment Rescues Trafficking and Processing of a Mutant Surfactant Protein–C

4-Phenylbutyric Acid Treatment Rescues Trafficking and Processing of a Mutant Surfactant Protein–C

Endoplasmic reticulum stress in lung disease

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

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