| First Author | Venosa A | Year | 2019 |
| Journal | J Immunol | Volume | 202 |
| Issue | 9 | Pages | 2760-2771 |
| PubMed ID | 30910861 | Mgi Jnum | J:274897 |
| Mgi Id | MGI:6296856 | Doi | 10.4049/jimmunol.1900039 |
| Citation | Venosa A, et al. (2019) Epithelial Expression of an Interstitial Lung Disease-Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice. J Immunol 202(9):2760-2771 |
| abstractText | Patients with idiopathic pulmonary fibrosis (IPF) often experience precipitous deteriorations, termed "acute exacerbations" (AE), marked by diffuse alveolitis and altered gas exchange, resulting in a significant loss of lung function or mortality. The missense isoleucine to threonine substitution at position 73 (I73T) in the alveolar type 2 cell-restricted surfactant protein-C (SP-C) gene (SFTPC) has been linked to clinical IPF. To better understand the sequence of events that impact AE-IPF, we leveraged a murine model of inducible SP-C(I73T) (SP-C(I73T/I73T)Flp(+/-) ) expression. Following administration of tamoxifen to 8-12-wk-old mice, an upregulation of Sftpc(I73T) initiated a diffuse lung injury marked by increases in bronchoalveolar lavage fluid (BALF) protein and histochemical evidence of CD45(+) and CD11b(+) cell infiltrates. Flow cytometry of collagenase-digested lung cells revealed a transient, early reduction in SiglecF(hi)CD11b(low)CD64(hi)CD11c(hi) macrophages, countered by the sequential accumulation of SiglecF(lo)CD11b(+)CD64(-)CD11c(-)CCR2(+)Ly6C(+) immature macrophages (3 d), Ly6G(+) neutrophils (7 d), and SiglecF(hi)CD11b(hi)CD11c(lo) eosinophils (2 wk). By mRNA analysis, BALF cells demonstrated a time-dependent phenotypic shift from a proinflammatory (3 d) to an anti-inflammatory/profibrotic activation state, along with serial elaboration of monocyte and eosinophil recruitment factors. The i.v. administration of clodronate effectively reduced total BALF cell numbers, CCR2(+) immature macrophages, and eosinophil influx while improving survival. In contrast, resident macrophage depletion from the intratracheal delivery of clodronate liposomes enhanced Sftpc(I73T) -induced mortality. These results using Sftpc(I73T) mice provide a detailed ontogeny for AE-IPF driven by alveolar epithelial dysfunction that induces a polycellular inflammation initiated by the early influx of proinflammatory CCR2(+)Ly6C(hi) immature macrophages. |
