ABSTRACT Aberrant immune response to injury is a major pathogenic driver of adverse extracellular matrix remodeling after acute lung injury (ALI) and a wide range of fibrotic lung diseases (referred to inflammation-fibrosis axis). However, there is currently no established approach for noninvasive assessment of dysregulated lung inflammation. This gap along with the pathophysiological heterogeneity and variability of the clinical course of patients has hampered precision medicine management of fibrotic lung diseases. Chemokine-like receptor-1 (CMKLR1) is chemokine receptor which is overexpressed in profibrotic monocyte-derived macrophages, a leukocyte subset with crucial roles in the pathogenesis of lung fibrosis. Our central goal is to determine the potential of CMKLR1-targeted PET for i) quantitative imaging of lung inflammation; ii) prognostication of the risk of disease progression; and iii) early monitoring of the response to anti-inflammatory and anti- fibrotic interventions in experimental models of ALI and fibrotic lung injury. We will also address the clinical relevance of CMKLR1-targeted PET and its potential for future clinical translation by determining the expression of CMKLR1 in the lungs of patients with COVID-19 and several categories of fibrotic lung diseases vs. healthy controls. Our preliminary data revealed a significant increase in lung uptake of a novel CMKLR1-targeted tracer (64Cu-NODAGA-CG34) in two murine models of lipopolysaccharide-induced ALI and bleomycin-induced fibrotic lung injury, which was primarily driven by the accumulation of monocyte-derived macrophages. Our central hypothesis is that i) CMKLR1 serves as a biomarker of monocyte-derived macrophages in ALI and fibrotic lung diseases; hence its targeted imaging by 64Cu-NODAGA-CG34 PET allows for ii) predicting the risk of progression into sustained inflammation and fibrosis; and iii) monitoring the early therapeutic response to anti-inflammatory and anti-fibrotic interventions. We propose three Specific Aims: Specific Aim 1: To determine the immunoprofile of CMKLR1-expressing leukocytes in A) murine models of ALI and fibrotic injury, and B) lung specimens of patients with COVID-19 and fibrotic lung diseases. Specific Aim 2: To validate the accuracy of CMKLR1-targeted PET as a biomarker of inflammation at different stages of ALI and fibrotic injury in murine models. Specific Aim 3: To determine the potential of CMKLR1-targeted PET in A) disease prognostication; and B) early detection of the therapeutic response in murine models of ALI and fibrotic lung injury. Impact: By determining the role of CMKLR1-targeted PET for imaging macrophage-driven inflammation and defining the expression of CMKLR1 across various fibrotic lung diseases, this proposal may lead to a precision medicine strategy that allows for i) improved risk stratification; ii) prospective identification of patients with a high likelihood of favorable response to anti-inflammatory/anti-fibrotic interve...