Abstract
Pulmonary fibrosis is a progressive, terminal disease with high mortality. Existing therapeutics are capable of slowing disease progression but are unable to reverse fibrotic lung remodeling, accentuating the importance of studying the mechanisms that underlie lung resilience and repair during fibrosis. Recent literature has suggested that alveolar type 2 (AT2) progenitors undergo transition to stressed Krt8(high) cells following lung injury. Accumulation of these stressed Krt8(high) cells has been observed in multiple acute and chronic lung diseases, particularly pulmonary fibrosis. Whether accumulation of Krt8(high) cells is a direct driver of fibrosis or an epiphenomenon of lung injury remains unclear. We have previously described a genetic model causing transition of AT2 progenitors to a Krt8(high) cell state following deletion of the lung transcription factor Nkx2-1 specifically in the AT2 progenitor lineage. Here, we use this tractable model of genetic Krt8(high) cell accumulation to directly evaluate the pathogenic influence of Krt8(high) cells which are present at the onset of lung fibrosis. Building on recent data, we show that these Nkx2-1(-/-) Krt8(high) cells accumulate in a Krt7(high)/Krt19(high)/Krt17(neg) alveolar-basal intermediate state (ABI). Following induction of fibrotic lung injury with inhaled silica, these ABI enter a unique inflammatory state (iABI) that drives severe fibrotic remodeling of the lung via coordination of a fibrotic signaling niche containing inflammatory alveolar fibroblasts (iAF) and pulmonary osteoclast-like cells (POLC). Computational analysis suggests that iABI elaborate pro-inflammatory signals which increase matrix deposition by iAF and drive differentiation of interstitial macrophages to a highly fibrotic POLC-like state. Niche mapping demonstrates that iABI, iAF, and POLCs interact within newly formed fibrotic niches in the lung alveolus, driving widespread fibrosis in animals with pre-existing accumulation of ABI. These data support the conclusion that ABIs actively participate in driving fibrosis after silica-induced lung injury, providing direct evidence that ABI accumulation in fibrotic lung disease is likely pathogenic.