Airway diseases affect more than 800 million people worldwide. Chronic Obstructive Pulmonary Disease (COPD) is a chronic and progressive lung disease involving emphysema, airway fibrosis and bronchiolitis, in which corticosteroids show little to no efficacy. We have discovered that the myeloid cytokine granulocyte-colony stimulating factor (G-CSF) is a critical mediator of COPD and a major contributor to COPD comorbidities. In animal models, we have found that genetically deleting G-CSF ablates not only lung disease but more remarkably, has a major impact on the development and progression of debilitating disease comorbidities. Effective therapies for COPD are lacking, and although anti-cytokine antibody-based therapeutics are garnering momentum in disease treatment, a significant issue for treatment of the diseased lung is successful delivery into inflamed regions. To overcome this issue, we have applied a different approach and utilize a small virus known as an Adeno-Associated Virus (AAV) which infects humans and mice but does not cause disease. AAVs are emerging as a promising gene therapy approach for respiratory disease because they specifically infect the lung, provide stable expression of inserted genes, and do not induce inflammation or disease. This approach has had success in therapeutic trials and is now being considered for the treatment of lung diseases such as cystic fibrosis. Using genetic cloning and molecular biology technologies, we have generated an AAV that produces a soluble G-CSFR. The AAV was administered trans-nasally to treat mice with established inflammatory lung disease, with an AAV encoding a non-binding receptor used as a control. Pathogenic levels of G-CSF produced in the chronically inflamed lung are specifically blocked by soluble G-CSFR, providing a novel treatment modality for this severe and chronic inflammatory disease.