2.2 Anti-innate immune system properties of furosemide
In 1988, Bianco and co-workers noted that exercise-induced bronchoconstriction in asthmatic patients was alleviated by inhaled furosemide, but not by orally administered furosemide. Since then, furosemide has been investigated as a possible treatment for symptomatic dyspnoea, initially based on the assumption that the size of edematous airway mast cells would be reduced by cellular diuresis thereby improving airway patency. However, multiple mechanistic studies have reported that furosemide’s effects on dyspnoea is not related to a local diuretic activity mediated via the Na+/K+/Cl-cotransporter; instead, current evidence indicates that this therapeutic effect arises from reduced secretion of pro-inflammatory cytokines, specifically IL-6, IL-8 and TNFα. In two studies by Yuengsrigul et al. (1996, 1999) peripheral blood mononuclear cells (PBMCs) from healthy subjects were isolated, stimulated with lipopolysaccharide (LPS) and treated with furosemide. It was found that levels of IL-6, IL-8 and TNFα from furosemide treated cells were significantly reduced compared to PBMCs not treated with furosemide. Similar results by Xu et al. (2006) report reduced production of the pro-inflammatory cytokines IL-6 and TNFα in pre-eclamptic placentas and PBMCs. Also, our group has recently shown inhibition of pro-inflammatory cytokine production as well as promotion of anti-inflammatory markers by furosemide in multiple macrophage cell lines of the human innate immune system. These findings are supported by multiple clinical trials studying the reduced secretion of pro-inflammatory cytokines in patients with bronchopulmonary dysplasia, tachypnoea, and chronic lung disease upon administration of inhaled furosemide.
Other clinical studies have reported beneficial anti-inflammatory and symptomatic effects of inhaled furosemide in experimentally induced air hunger and breathing discomfort. In a double-blind, placebo-controlled clinical trial by Grogono et al. (2018), the effect of 40 mg inhaled furosemide was tested on the sensation of experimentally induced air hunger and work effort. It was found that air hunger in healthy individuals is significantly relieved by inhaled furosemide, while this was not the case with inhaled saline control. These results support the study of Moosvai et al. (2007) who had conducted a similar trial on the air hunger sensation; they, too, reported that air hunger is relieved by inhalation of 40 mg furosemide. Yet another study reporting that furosemide alleviates the sensation of dyspnoea was conducted by Nishino and co-workers (2000): in 12 healthy subjects, severe dyspnoeic sensation was induced by breath holding and loaded breathing with a combination of inspiratory resistive load and hypercapnia. It was found that after inhalation of furosemide (and compared to the inhalation of a placebo), total breath holding time was prolonged and respiratory discomfort during loaded breathing developed more slowly. Multiple other studies have reported the positive effects of inhaled furosemide in attenuating bronchoconstriction and asthma attacks, presumably via an anti-inflammatory mechanism.
In contrast, a single study by Banzett et al. (2017) reported that in 11 healthy volunteers the reduction of breathing discomfort by 80 mg inhaled furosemide was only slightly greater than that of an inhaled saline solution; in fact, both furosemide and saline placebo aerosols alleviated the breathing discomfort to a very similar, clinically relevant extent.