Abstract Body (Do not enter title and authors here): Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by excessive collagen deposition and progressive loss of lung compliance. The prognosis is usually poor and therapeutic options are limited. Recurrent damage to the alveolar surfactant lipid-producing type 2 cells (T2C) is a key driver of PF initiation.
Recent data from our lab has showed that mice with T2C-specific loss of low-density lipoprotein receptor-related protein-1 (SPC-LRP1^-/-) exhibit reduced pulmonary compliance and decreased levels of surfactant lipids at baseline. We hypothesized that LRP1 deficiency in T2C predisposes the alveolar environment to fibrotic remodeling.
We challenged 6-months old wild-type (WT) and SPC-LRP1^-/- male mice with repeated low-dose bleomycin (BLM), a well-established profibrotic agent. Mice were euthanized 33 days after the initiation of the BLM challenge. Inflammation was monitored through weekly body weight measurements and by bronchoalveolar lavage (BAL) protein concentration after euthanasia. Pulmonary function was evaluated longitudinally and after euthanasia. Paraffin sections were prepared, pulmonary fibrosis was assessed using the Ashcroft Grade scoring system, and emphysema was quantified via mean linear intercept (MLI). BAL lipid composition was analyzed using mass spectrometry.
As the BLM challenge progressed, WT mice showed increased tidal volume and peak inspiratory flow, while the timing between early and late expiration was reduced. In contrast SPC-LRP1 ^-/- mice showed increased expiratory time and end expiratory pause, with decreased respiratory frequency. Despite these differences, static compliance, inspiratory capacity and forced vital capacity were similarly decreased in both WT and SPC-LRP1^-/- mice at the end of the BLM challenge, which suggested similar restrictive defects in pulmonary function. However, histological analysis showed higher degree of fibrosis and decreased MLI in SPC-LRP1^-/- mice, depicting coexisting emphysematous and fibrotic remodeling. BAL lipid profiling showed lower concentration of surfactant phosphatidylcholine (PC) and of other lipid groups in SPC-LRP1^-/- than in WT mice, suggesting impaired T2C surfactant lipid metabolism. SPC-LRP1^-/- also had higher BAL protein concentration than WT mice, indicating increased inflammation.
The data suggest that loss of LRP1 in T2C promotes emphysema and exacerbates BLM-induced fibrosis and inflammation.