Table 1 Summary of in vitro co-culture and conditioned medium model studies assessing immune-fibroblast interactions in the pathogenesis of idiopathic pulmonary fibrosis

Direct coculture 2D and 3D on plates or decellularized lung scaffolds and

CM

LAD2 mast cell line directly cocultured with PHLF’s or HFL-1

Mast cell tryptase,

Mast cell Chymase,

Fibrogenic release of VEGF, HGF and IL-6

Upregulation of ECM proteins and growth factors that prevent apoptosis of endothelial and epithelial cells and contribute to the stiffening of the lung tissue. Increase in fibroblast migration. Contributes to inflammatory mechanisms by attracting neutrophils

[38]

Direct coculture

HLF’s isolated from control or IPF lungs cultured with primary human mast cells on tissue culture plates

Mast cell release of tryptase,

Fibrogenic fibronectin and collagen I release

Increased release of fibrogenic ECM proteins contributes to the fibrosis of lung tissue. Increased proliferation of fibroblasts

[41]

Direct co-culture and indirect transwell co-culture

Direct co-culture in 3D hydrogels

CM

IPF and control-derived primary alveolar macrophages and lung fibroblasts

Macrophage release of CCL2

Fibrogenic release of fibronectin collagen I &III

Contributes to inflammatory mechanisms by attracting immune cells.

Increase ECM proteins, potential myofibroblast differentiation.

[42]

CM

Primary IPF fibroblasts with THP-1 macrophages, treated with FasL to induce apoptosis

MDM4 gene expression regulates P53 activation of DD1α receptor on macrophages.

Macrophage release of CX3CL1 and CXCL10

Improper clearing of apoptotic cells on stiff matrices. Chemokines and cytokines attract immune cells.

[43]

Neutrophil derivative Exposure model

Lung fibroblasts exposed to Neutrophil Elastase (NE).

Neutrophil elastase stimulate fibrogenic release of pSMAD3 & α-SMA. Loss of the insulin receptor substrate (IRS)-1, an intracellular mediator of phosphatidylinositol-3 kinase (PI3K) signalling

Increase in fibrogenic phenotype of fibroblasts. Increase in fibroblast proliferation

[48]

CM

IPF-derived fibroblasts exposed to CM from B cell stimulated with bacterial antigens (β-glucan & CpG)

Fibrogenic increase in the expression of of PAI1, α -SMA and fibronectin

Upregulation of ECM proteins, increase in fibroblast migration.

Nintedanib treated B-cell CM decreased migration of lung fibroblasts and fibrogenic phenotype

[51]

CM

Lung fibroblasts exposed to CM from IPF-derived primary T cells

Authors suggested this could be due to factors such as PGE2

Increase in fibroblast collagen production and proliferation

[52]

Direct co-culture

Indirect transwell coculture

IPF derived T cells co-cultured with control and IPF-derived fibroblasts

Decreased calponin and α -SMA

T cells decrease myofibroblast differentiation induced by TGF-β.

[53]

Direct co-culture and CM

PBdMC and LAD2 mast cells with HFL-1 lung fibroblasts

Mast Cell Tryptase

Increased fibroblast migration and proliferation

[54]

CM

Healthy human primary T cells exposed to CM from IPF-derived primary lung fibroblasts

High concentration of pro-apoptotic proteins in fibroblast CM including Pro-caspase 3, cytochrome C, HIF-1 α and TNFR1

Increase in CD4 + and CD8 + cell death, decrease in T cell migration after chemokine exposure.

[61]

Direct and indirect co-cultures

IPF and control-derived primary human lung fibroblasts and alveolar macrophages co-cultures

Alveolar Macrophage release of the chemokine CCL18

Potentiates inflammation by attracting adaptive immune cells

[65]

Neutrophil derivative Exposure model

HNP-1 exposed to normal human lung fibroblasts

Fibrogenic release of IL-8

Leads to the recruitment and activation of neutrophils

[70]

Direct co-culture

Co-culture of cord blood-derived mast cells (CBMCs) with normal human lung fibroblasts on collagen coated plates

Mast Cell Stem Cell Factor release

Addition of Nintedanib abolished lung fibroblast induced mast cell survival

[79]