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Am J Physiol Lung Cell Mol Physiol. 2018 May 1;314(5):L882-L892. doi: 10.1152/ajplung.00418.2017. Epub 2018 Jan 18.

Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair.

Author information

1
Department of Cell Biology, Yale School of Medicine , New Haven, Connecticut.
2
Yale Stem Cell Center, Yale University , New Haven, Connecticut.
3
Department of Regenerative Medicine, Centre for Preclinical Research and Technology, Medical University of Warsaw , Warsaw , Poland.
4
Department of Pathology, Yale School of Medicine , New Haven, Connecticut.
5
Department of Laboratory Medicine, Yale School of Medicine , New Haven, Connecticut.
6
Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine , New Haven, Connecticut.
7
Department of Comparative Medicine, Yale School of Medicine , New Haven, Connecticut.
8
Department of Pediatrics, Yale School of Medicine , New Haven, Connecticut.

Abstract

Surfactant protein C (SPC), a key component of pulmonary surfactant, also plays a role in regulating inflammation. SPC deficiency in patients and mouse models is associated with increased inflammation and delayed repair, but the key drivers of SPC-regulated inflammation in response to injury are largely unknown. This study focuses on a new mechanism of SPC as an anti-inflammatory molecule using SPC-TK/SPC-KO (surfactant protein C-thymidine kinase/surfactant protein C knockout) mice, which represent a novel sterile injury model that mimics clinical acute respiratory distress syndrome (ARDS). SPC-TK mice express the inducible suicide gene thymidine kinase from by the SPC promoter, which targets alveolar type 2 (AT2) cells for depletion in response to ganciclovir (GCV). We compared GCV-induced injury and repair in SPC-TK mice that have normal endogenous SPC expression with SPC-TK/SPC-KO mice lacking SPC expression. In contrast to SPC-TK mice, SPC-TK/SPC-KO mice treated with GCV exhibited more severe inflammation, resulting in over 90% mortality; there was only 8% mortality of SPC-TK animals. SPC-TK/SPC-KO mice had highly elevated inflammatory cytokines and granulocyte infiltration in the bronchoalveolar lavage (BAL) fluid. Consistent with a proinflammatory phenotype, immunofluorescence revealed increased phosphorylated signal transduction and activation of transcription 3 (pSTAT3), suggesting enhanced Janus kinase (JAK)/STAT activation in inflammatory and AT2 cells of SPC-TK/SPC-KO mice. The level of suppressor of cytokine signaling 3, an anti-inflammatory mediator that decreases pSTAT3 signaling, was significantly decreased in the BAL fluid of SPC-TK/SPC-KO mice. Hyperactivation of pSTAT3 and inflammation were rescued by AZD1480, a JAK1/2 inhibitor. Our findings showing a novel role for SPC in regulating inflammation via JAK/STAT may have clinical applications.

KEYWORDS:

JAK/STAT; alveolar macrophages; alveolar type 2 cells; inflammation; surfactant protein C

PMID:
29345196
PMCID:
PMC6008135
DOI:
10.1152/ajplung.00418.2017
[Indexed for MEDLINE]
Free PMC Article

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