scholarly journals Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandro Venosa ◽  
Sophie Cowman ◽  
Jeremy Katzen ◽  
Yaniv Tomer ◽  
Brittnie S. Armstrong ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Mrna Expression ◽  
Protein C ◽  
Cell Activation ◽  
Surfactant Protein ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Genetic Ablation ◽  
Surfactant Protein C

Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. FACS analysis of CD11b+CD64-Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T induced injury reveals dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

scholarly journals Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred

2011 ◽  
Vol 38 (4) ◽  
pp. 861-869 ◽  
Author(s):  
S. Ono ◽  
T. Tanaka ◽  
M. Ishida ◽  
A. Kinoshita ◽  
J. Fukuoka ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein C ◽  
Surfactant Protein ◽  
Surfactant Protein C ◽  
Familial Pulmonary Fibrosis

The role of pulmonary surfactant protein C during the breathing cycle

1998 ◽  
Vol 327-329 ◽  
pp. 632-635 ◽  
Author(s):  
H.-J. Galla ◽  
N. Bourdos ◽  
A. von Nahmen ◽  
M. Amrein ◽  
M. Sieber
Keyword(s):  
Pulmonary Surfactant ◽  
Protein C ◽  
Surfactant Protein ◽  
Breathing Cycle ◽  
Surfactant Protein C ◽  
Pulmonary Surfactant Protein

Surfactant Protein C in Canine Pulmonary Fibrosis

2009 ◽  
Vol 23 (6) ◽  
pp. 1170-1174 ◽  
Author(s):  
M. Eriksson ◽  
H. von Euler ◽  
E. Ekman ◽  
K. Nordling ◽  
J. Häggström ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein C ◽  
Surfactant Protein ◽  
Surfactant Protein C

Autophagy regulates hyperoxia-induced intracellular accumulation of surfactant protein C in alveolar type II cells

2015 ◽  
Vol 408 (1-2) ◽  
pp. 181-189 ◽  
Author(s):  
Liang Zhang ◽  
Shuang Zhao ◽  
Li-Jie Yuan ◽  
Hong-Min Wu ◽  
Hong Jiang ◽  
...  
Keyword(s):  
Protein C ◽  
Surfactant Protein ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Intracellular Accumulation ◽  
Alveolar Type Ii Cells ◽  
Surfactant Protein C

scholarly journals Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

2005 ◽  
Vol 167 (5) ◽  
pp. 1267-1277 ◽  
Author(s):  
William E. Lawson ◽  
Vasiliy V. Polosukhin ◽  
Georgios T. Stathopoulos ◽  
Ornella Zoia ◽  
Wei Han ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein C ◽  
Surfactant Protein ◽  
Surfactant Protein C ◽  
Deficient Mice

scholarly journals Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant

2021 ◽  
pp. 2100267
Author(s):  
Jennifer A. Dickens ◽  
Eimear N. Rutherford ◽  
Susana Abreu ◽  
Joseph E. Chambers ◽  
Matthew O. Ellis ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Cell Surface ◽  
Protein C ◽  
Alveolar Epithelial Cell ◽  
Surfactant Protein ◽  
Surfactant Protein C ◽  
Alveolar Epithelial ◽  
Health And Disease

Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic-gain-of-function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids.We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.

Localization of Misprocessed Pulmonary Surfactant Protein C in Tubular Myelin Enriched Fractions By Cryo Immunogold Labeling

2000 ◽  
Vol 6 (S2) ◽  
pp. 868-869
Author(s):  
C.-L. Na ◽  
E. A. Evans ◽  
H. T. Akinbi ◽  
T. E. Weaver
Keyword(s):  
Pulmonary Surfactant ◽  
Protein C ◽  
Intracellular Localization ◽  
Surfactant Protein ◽  
Biologically Active ◽  
Alveolar Type ◽  
Double Knockout ◽  
Surfactant Protein C ◽  
Associated Proteins ◽  
Pulmonary Surfactant Protein

Pulmonary surfactant is secreted by alveolar type II cells and reduces the surface tension at the air-liquid interface of alveoli. After pulmonary surfactant is secreted into the alveolar space, it transforms into tubular myelin, a highly ordered 3-dimensional lattice-like structure. Pulmonary surfactant protein C (SP-C), one of four pulmonary surfactant associated proteins, is synthesized as a proprotein which is processed to biologically active 35 amino acid mature peptide by proteolytic cleavage of N- and C-terminal peptides from the SP-C propeptide (Weaver, 1998). Processing of SP-C is linked to the expression of pulmonary surfactant protein B (SP-B): In SP-B deficient mice, SP-C is misprocessed and present in the bronchoalveolar lavage (BAL; Vorbroker et. al., 1995a). Although the intracellular localization of SP-C is well established (Vorbroker et. al., 1995b), there is no ultrastructure study available regarding the localization of misprocessed SP-C in the airway. In this study, we used transgenic mice expressing a truncated human SP-B propeptide (hSP-BΔC+/+) bred into the murine granulocyte macrophage colony stimulating factor (GMCSF) and SP-B double knockout background (hSP-BΔC+/+: GMCSF-/-: mSP-B-/-) as a model to localize the misprocessed SP-C by cryoimmunogold labeling.

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