Adenosine-Dependent Pulmonary Fibrosis in Adenosine Deaminase-Deficient Mice

Abstract

Pulmonary fibrosis is a common feature of numerous lung disorders, including interstitial lung diseases, asthma, and chronic obstructive pulmonary disease. Despite the prevalence of pulmonary fibrosis, the molecular mechanisms governing inflammatory and fibroproliferative aspects of the disorder are not clear. Adenosine is a purine-signaling nucleoside that is generated in excess during cellular stress and damage. This signaling molecule has been implicated in the regulation of features of chronic lung disease; however, the impact of adenosine on pulmonary fibrosis is not well understood. The goal of this study was to explore the impact of endogenous adenosine elevations on pulmonary fibrosis. To accomplish this, adenosine deaminase (ADA)-deficient mice were treated with various levels of ADA enzyme replacement therapy to regulate endogenous adenosine levels in the lung. Maintaining ADA-deficient mice on low dosages of ADA enzyme therapy led to chronic elevations in lung adenosine levels that were associated with pulmonary inflammation, expression of profibrotic molecules, collagen deposition, and extreme alteration in airway structure. These features could be blocked by preventing elevations in lung adenosine. Furthermore, lowering lung adenosine levels after the establishment of pulmonary fibrosis resulted in a resolution of fibrosis. These findings demonstrate that chronic adenosine elevations are associated with pulmonary fibrosis in ADA-deficient mice and suggest that the adenosine functions as a profibrotic signal in the lung.

Identification of Ectonucleotidases CD39 and CD73 in Innate Protection during Acute Lung Injury

“…In addition, ADA-deficient mice develop signs of chronic pulmonary injury in association with chronically elevated pulmonary adenosine levels. In fact, ADAdeficient mice die within weeks after birth from severe respiratory distress (42) and recent studies suggest that attenuation of adenosine signaling may reverse the severe pulmonary phenotypes in ADA-deficient mice, suggesting that chronic adenosine elevation can affect signaling pathways that mediate aspects of chronic lung disease (36,37).…”

Adenosine in fibrosis

“…Significant elevations in transcript levels of adenosine A 1 and A 2B receptors were also reported [64]. These changes correlated with histo-logically demonstrable fibrosis with an increased number of pulmonary myofibroblasts and collagen deposition following staining with Masson’s trichrome as well as semi-quantitative assessment of fibrosis by Ashcroft’s fibrosis scoring system [60, 64]. Excessive collagen deposition was not limited to the lungs, but was also seen in the liver and kidney glomeruli.…”

“…These mice were developed in their laboratory, and targeted gene deletion resulting in the deficiency of a key enzyme that catabolizes adenosine into inosine renders both circulating and tissue adenosine levels extremely high [60, 61]. One of the potential benefits of using this model is that adenosine deaminase enzyme therapy can be administered by injection to these mice, much as it is used as therapy for adenosine deaminase in humans, thus enabling direct manipulation of tissue adenosine levels through varying the dose of adenosine deam-inase injected.…”

Changes in Adenosine Metabolism in Asthma. A Study on Adenosine, 5&#39-NT, Adenosine Deaminase and Its Isoenzyme Levels in Serum, Lymphocytes and Erythrocytes

“…Activation of the A2BR on human lung fibroblasts increases the release of IL-6 and induces differentiation into myofibroblasts suggesting that adenosine, via A2BR participates in the remodelling process occurring in chronic lung diseases [64]. Chunn et al revealed that controlling adenosine levels with the use of exogenous ADA treatments may provide a significant approach to seize the progression or alter the features of pulmonary fibrosis in severe asthma [65]. …”