<p>Purpose: Calcitonin gene-related peptide (CGRP) regulates inflammation through receptor activity-modifying protein 1 (RAMP1), a subunit of CGRP receptor complex in immune cells. Acute respiratory distress syndrome (ARDS) is a severe respiratory dysfunction induced by cytokine storm that leads to alveolar epithelial damage and increased pulmonary vascular permeability. This study investigated the role of RAMP1 signaling in the pathology of ARDS.</p><p>Methods and Results: ARDS was created by an intratracheal administration of lipopolysaccharide (LPS) to male RAMP1-knockout (RAMP1-/-) mice and wild-type (WT) mice. As compared with WT, RAMP1-/- exhibited increases in fatality rates, infiltration of inflammatory cells and hemorrhage in the lung tissues, and levels of total protein, inflammatory cytokines (TNFα, IL-1β and, IL-6), and chemokine (CXCL12) in bronchoalveolar lavage fluid (BALF). RAMP1 was expressed in alveolar macrophages (AMs), and CGRP levels in BALF were increased in WT and RAMP1-/- at 72 h. Removal of AMs with clodronate liposome (CL) enhanced lung injury and total protein levels, and reduced cytokines (TNFα and IL-1β) in both genotypes at 6 h, but increased the cytokines and CXCL2 together with neutrophil accumulation at 72 h. Cultured AMs from RAMP1-/- showed higher levels of cytokines and chemokines than those in WT.</p><p>Conclusion: These results suggested that deletion of RAMP1 signaling in AMs aggravated LPS-induced acute lung injury by increasing vascular permeability, inflammatory cytokines production, and neutrophil accumulation.</p>