Malondialdehyde-acetaldehyde (MAA) adducted surfactant protein induced lung inflammation is mediated through scavenger receptor a (SR-A1)

Abstract

BackgroundCo-exposure to cigarette smoke and alcohol leads to the generation of high concentrations of acetaldehyde and malondialdehyde in the lung. These aldehydes being highly electrophilic in nature react with biologically relevant proteins such as surfactant protein D (SPD) through a Schiff base reaction to generate SPD adducted malondialdehyde-acetaldehyde adduct (SPD-MAA) in mouse lung. SPD-MAA results in an increase in lung pro-inflammatory chemokine, keratinocyte chemoattractant (KC), and the recruitment of lung lavage neutrophils. Previous in vitro studies in bronchial epithelial cells and macrophages show that scavenger receptor A (SR-A1/CD204) is a major receptor for SPD-MAA. No studies have yet examined the in vivo role of SR-A1 in MAA-mediated lung inflammation. Therefore, we hypothesize that in the absence of SR-A1, MAA-induced inflammation in the lung is reduced or diminished.MethodsTo test this hypothesis, C57BL/6 WT and SR-A1 KO mice were nasally instilled with 50 μg/mL of SPD-MAA for 3 weeks (wks). After 3 weeks, bronchoalveolar lavage (BAL) fluid was collected and assayed for a total cell count, a differential cell count and CXCL1 (KC) chemokine. Lung tissue sections were stained with hematoxylin and eosin (H&E) and antibodies to MAA adduct.ResultsResults showed that BAL cellularity and influx of neutrophils were decreased in SR-A1 KO mice as compared to WT following repetitive SPD-MAA exposure. MAA adduct staining in the lung epithelium was decreased in SR-A1 KO mice. In comparison to WT, no increase in CXCL1 was observed in BAL fluid from SR-A1 KO mice over time.ConclusionsOverall, the data demonstrate that SR-A1/CD204 plays an important role in SPD-MAA induced inflammation in lung.

Alpha-Fetoprotein Binding Mucin and Scavenger Receptors: An Available Bio-Target for Treating Cancer

“…Ligand binding to SR-A1 can also induce tumor cell growth. These characteristics further support SR-A1 as a cell-surface receptor for AFP (29,85,86,(96)(97)(98). Another SR that may be candidate as an AFPR is the mannose receptor (CD206, or MR), which plays an important role in the immune response (99,100).…”

“…SR-A1 may also be a cell-surface receptor for AFP which are belong to class SRs-A, whose isoforms are largely expressed on macrophages but can also be detected on endothelial and smooth muscle tissues (29,85). SR-A1 can cause the tyrosine phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase), and SR-A1 activates signaling pathways involving protein kinase C (PKC), ERK, JNK, caspases and cytokine secretion (85,86,(96)(97)(98). Ligand binding to SR-A1 can also induce tumor cell growth.…”

Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial

“…10 Primarily by binding to thiol and amine residues on proteins, RASP are precytokine mediators of inflammation that, in addition to potentiating cytokine release, activate inflammasomes and are ligands for scavenger receptor A. [11][12][13][14] In contrast to RASP-mediated inflammatory factors, the presence of histamine is transient, particularly due to the activity of histaminase. 15 Following peak histamine levels in tears approximately 5 minutes after allergen challenge, post-acute factors, including cellular infiltrate, cytokines, and other RASP-mediated inflammatory mediators, may perpetuate the signs and symptoms of allergic conjunctivitis.…”

Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement

“…[3][4][5][6][7][8][9] By covalently binding amino and thiol groups on receptors and kinases, RASP potentiate upstream proinflammatory signaling cascades that involve NF-kB, inflammasomes, scavenger receptor A, and other mediators. [16][17][18][19] Increased levels of RASP are implicated across diverse ophthalmic inflammatory conditions, including anterior uveitis, 10 Behçet disease, 11 cataracts, 12 pterygium, 13 glaucoma, 14 and proliferative vitreoretinopathies. 15 Findings from these studies suggest that RASP represent a potential therapeutic target for ocular inflammatory diseases.…”