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

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Intercellular Signaling Peptides and Proteins
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism*
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Lung Injury / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / physiology*
  • Phosphorylation
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Pneumonia / prevention & control*
  • Pulmonary Surfactant-Associated Protein C
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Thymidine Kinase / physiology*


  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Pulmonary Surfactant-Associated Protein C
  • STAT3 Transcription Factor
  • Sftpc protein, mouse
  • Stat3 protein, mouse
  • Thymidine Kinase
  • Jak1 protein, mouse
  • Janus Kinase 1