Broad-Spectrum Protective Effects of Lyophilized FE002-Lu Lung Fibroblast Conditioned Medium Against Acute and Chronic Pulmonary Injury in Wistar Rats

Background: While live-cell therapies face significant translational hurdles, cell-free secretomes derived from fetal progenitor cells offer a unique, scalable approach natively programmed for scarless tissue repair. Methods: This GLP-compliant study evaluated the therapeutic efficacy spectrum of an off-the-shelf, clinical-grade, intratracheal lyophilized FE002-Lu lung fibroblast conditioned medium (LFCM) across five controlled Wistar rat models of induced lung injury: bleomycin (5 mg/kg), asbestos (100 µg/rat), hyperoxia (100% oxygen exposure), silica (30 mg/rat), and lipopolysaccharide (LPS, 4 mg/kg). Following lung injury induction and symptom onset, symptomatic rats were randomized to receive intratracheal LFCM (low, mid, or high dose) or a vehicle control every 4 days for 28 days. Results: The intervention demonstrated an exceptional safety profile, maintaining 100% survival with no severe procedural toxicity across all cohorts. Across all study arms, LFCM effectively attenuated pulmonary inflammation, reducing pro-inflammatory markers (IL-1β, IL-6, TNF-α, and CINC-1) in bronchoalveolar lavage fluid. Concurrently, high LFCM doses consistently elevated the anti-inflammatory cytokine IL-10. Within the lung tissue, mid- and high doses significantly reduced key pro-fibrotic drivers, including TGF-β1, TIMP-1, WISP-1, and hydroxyproline. Treatments consistently decreased α-SMA expression and pro-fibrotic gene mRNA levels, mitigating pulmonary myofibroblast activation. This correlated with reduced Ashcroft scores and collagen deposition, thereby preserving lung architecture. Notably, the FE002-Lu LFCM treatment exerted a biphasic regulation of extracellular matrix turnover: it elevated Cathepsin-D and MMP-12 in the bleomycin arm to actively clear newly deposited fibrotic debris, while reducing these markers in the hyperoxia and LPS arms to prevent acute collateral degradation of the native lung matrix. In both particulate models (asbestos and silica), the LFCM mid-dose established an optimal therapeutic threshold, avoiding the localized secretome saturation and pro-fibrotic exacerbation occasionally observed at higher doses. Conclusions: Lyophilized FE002-Lu LFCM acts as a potent, pleiotropic biologic that effectively resolves acute pulmonary inflammation and arrests progressive fibrotic remodeling across multiple distinct in vivo models. By overcoming the cold-chain and delivery limitations inherent to pulmonary live-cell therapies, this stable, cell-free secretome represents a highly scalable, “off-the-shelf” candidate poised for non-invasive, aerosolized clinical translation.