Reactive aldehyde species (RASP), also known as reactive aldehydes, refer to a class of electrophilic organic aldehyde molecules that are generally toxic or facilitate
inflammation. RASP covalently react with
amine groups (via
Schiff base formation) and
thiol groups (via
Michael addition), particularly in
proteins.
[1] Following threshold amounts of binding to the electrophile-responsive
proteome, RASP modify
protein function,
[2] as has been described with
MAP kinase,
protein kinase C, and other proteins that potentiate
cytokine release and other aspects of
inflammation.
[3] Binding of RASP to proteins can also lead to
NF-kB activation,
[4]
autoantibody formation,
[5]
inflammasome activation,
[6] and activation of
Scavenger Receptor A.
[7] RASP are formed via a variety of processes, including
oxidation of
alcohols,
[8]
polyamine metabolism
[9] and
lipid peroxidation.
[1] In addition to binding to proteins and other
amine or
thiol-containing
molecules such as
glutathione, RASP are metabolized by
aldehyde dehydrogenases
[8] or
aldehyde reductases.
[9] Due to the toxicity of RASP, only a small number of
genetic mutations in
aldehyde dehydrogenases allow for viable offspring, resulting in
Sjögren-Larsson Syndrome,
[8]
Succinic Semi-Aldehyde Dehydrogenase Deficiency,
[10] and other
rare diseases.
The two most commonly reported disease-associated pro-inflammatory RASP are
malondialdehyde and
4-hydroxynonenal,
[11] although many others, including
acrolein,
crotonaldehyde,
acetaldehyde, and
hexanal, have been described.
[1] The toxicity of RASP include
mutagenicity, aggregate formation, and generalized
cytotoxicity.
[1]
[12]
Malondialdehyde, for example, has been associated with many inflammatory and
autoimmune diseases, including
asthma,
[13]
psoriasis,
[14] and
dry eye disease.
[15] Only two RASP,
retinaldehyde and
pyridoxal (or
pyridoxal phosphate), appear to effect essential non-inflammatory physiologic functions in animals, though
retinaldehyde is highly dependent on
protein chaperones to prevent toxicity.
[16]
In clinical trials, the RASP inhibitor reproxalap was shown to mitigate inflammation in patients with noninfectious
anterior uveitis,
[17]
dry eye disease
[18]
[19] and
allergic conjunctivitis.
[20]
[21]
[22]
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