Animal models of airway diseases

Abstract

Over the past 20 years, the growing awareness that purinergic signaling events literally shape the immune and inflammatory responses to infection and allergic reactions warranted the development of animal models to assess their importance in vivo in acute lung injury and chronic airway diseases. The pioneer work conducted with the adenosine deaminase (ADA)-deficient mouse provided irrefutable evidence that excess adenosine (ADO) accumulating in the lungs of asthmatic patients, constitutes a powerful mediator of disease severity. These original studies launched the development of murine strains for the two major ectonucleotidases responsible for the generation of airway ADO from ATP release: CD39 and CD73. The dramatic acute lung injury and chronic lung complications, manifested by these knockout mice in response to allergens and endotoxin, demonstrated the critical importance of regulating the availability of ATP and ADO for their receptors. Therapeutic targets are currently evaluated using knockout mice and agonists/antagonists for each ADO receptor (A(1)R, A(2A)R, A(2B)R, and A(3)R) and the predominant ATP receptors (P2Y(2)R and P2X(7)R). This chapter provides an in-depth description of each in vivo study, and a critical view of the therapeutic potentials for the treatment of airway diseases.

Fig. 8.1

Purinergic regulation of fluid fluxes and barrier permeability in the lung. In the circulation, nucleotides regulate endothelial permeability to fluid and leukocytes by the balancing activities of ATP, ADP and ADO receptors. Whereas P2Y₁R activation reduces the transmembrane electrical resistance (TER), P2Y₂Rs, A_2ARs and A_2BRs all protect the lungs against vascular leakage. A second barrier protects the airways against excess fluid accumulation: the epithelial barrier. Alveolar cells express A₁Rs and A_2ARs which regulate fluid fluxes in and out of the airspace along ion gradients generated by the CFTR chloride (Cl^–) channel and the ENaC sodium (Na⁺) channel. During viral infection, pulmonary edema is caused by the production, release and conversion of UTP into UDP, which activates P2Y₆Rs to inhibit Na⁺ and fluid absorption via ENaC

Fig. 8.2

Summary of the adenosine-mediated responses in murine models of acute lung injury and chronic lung disease. The blue boxes indicate anti-inflammatory and protective effects, the green boxes indicate pro-inflammatory and damaging responses