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.