Increased Ornithine-Derived Polyamines Cause Airway Hyperresponsiveness in a Mouse Model of Asthma

Abstract

Up-regulation of arginase contributes to airways hyperresponsiveness (AHR) in asthma by reducing L-arginine bioavailability for the nitric oxide (NO) synthase isozymes. The product of arginase activity, L-ornithine, can be metabolized into polyamines by ornithine decarboxylase. We tested the hypothesis that increases in L-ornithine-derived polyamines contribute to AHR in mouse models of allergic airways inflammation. After measuring significantly increased polyamine levels in sputum samples from human subjects with asthma after allergen challenge, we used acute and subacute ovalbumin sensitization and challenge mouse models of allergic airways inflammation and naive mice to investigate the relationship of AHR to methacholine and polyamines in the lung. We found that spermine levels were elevated significantly in lungs from the acute model, which exhibits robust AHR, but not in the subacute murine model of asthma, which does not develop AHR. Intratracheal administration of spermine significantly augmented airways responsiveness to methacholine in both naive mice and mice with subacute airways inflammation, and reduced nitrite/nitrate levels in lung homogenates, suggesting that the AHR developed as a consequence of inhibition of constitutive NO production in the airways. Chronic inhibition of polyamine synthesis using an ornithine decarboxylase inhibitor significantly reduced polyamine levels, restored nitrite/nitrate levels to normal, and abrogated the AHR to methacholine in the acute model of allergic airways inflammation. We demonstrate that spermine increases airways responsiveness to methacholine, likely through inhibition of constitutive NO synthesis. Thus, inhibition of polyamine production may represent a new therapeutic target to treat airway obstruction in allergic asthma.

Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway

“…Nonetheless, these data point to a novel mechanism by which hyperoxia may alter airway structure. It is also possible that hyperoxia-induced upregulation of arginase enhances ASM proliferation and hyperresponsiveness via an increase in ornithine-derived polyamines as reported in a mature mouse model of asthma (14). In summary, we have documented enhanced airway reactivity in neonatal mice that have recovered from modest hyperoxic exposure.…”

Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD)

“…Concentrations were determined by comparison with standard curves prepared and processed in a similar manner as the sputum samples. Sputum nitrite, NO x , and in vitro arginase activities were measured using spectrophotometric approaches, as described previously [16]. …”

“…Recent evidence suggests that arginase controls NOS activity in airways not only through limitation of l -arginine bioavailability, but also by producing l -ornithine, the precursor of polyamine biosynthesis [15,16]. The polyamine spermine, which acts as an inhibitor of NOS, is increased in asthma and CF airways [15,16].…”

“…The polyamine spermine, which acts as an inhibitor of NOS, is increased in asthma and CF airways [15,16]. We recently demonstrated in the mouse that nebulization of spermine into the airways led to airways hyperreponsiveness to methacholine, which was mediated via a decrease in airway NO [16].…”

“…The polyamine spermine, which acts as an inhibitor of NOS, is increased in asthma and CF airways [15,16]. We recently demonstrated in the mouse that nebulization of spermine into the airways led to airways hyperreponsiveness to methacholine, which was mediated via a decrease in airway NO [16]. The shift of l -arginine metabolism toward the arginase pathway has been suggested to contribute to remodeling of asthma airways, due to the production of polyamines [12,16] and of proline, which is a precursor of the deposition of collagen [1,14,17].…”