Single-Photon Emission Computed Tomography Imaging Using Formyl Peptide Receptor 1 Ligand Can Diagnose Aortic Aneurysms in a Mouse Model

Abstract

Background: Our previous studies showed that neutrophil infiltration and activation plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). However, there is a lack of noninvasive, inflammatory cell-specific molecular imaging methods to provide early diagnosis of AAA formation. Formyl peptide receptor 1 (FPR1) is rapidly upregulated on neutrophils during inflammation. Therefore, it is hypothesized that the use of cinnamoyl-F-(D)L-F-(D)L-F-K (cFLFLF), a PEGylated peptide ligand that binds FPR1 on activated neutrophils, would permit accurate and noninvasive diagnosis of AAA via singlephoton emission computed tomography (SPECT) imaging.Materials and methods: Male C57BL/6 (wild-type) mice were treated with topical elastase (0.4 U/mL type 1 porcine pancreatic elastase) or heat-inactivated elastase (control), and aortic diameter was measured by video micrometry. Comparative histology was performed on Day 14 to assess neutrophil infiltration in aortic tissue. We performed near-infrared fluorescence imaging using c-FLFLF-Cy7 probe on Days 7 and 14 postelastase treatment and measured fluorescence intensity ex vivo in excised aortic tissue. A separate group of animals were injected with 99m Tc-c-FLFLF 2 h before SPECT imaging on Day 14 using a SPECT/computed tomography/positron emission tomography trimodal scanner. Coexpression of neutrophils with c-FLFLF was also performed on aortic tissue by immunostaining on Day 14.Results: Aortic diameter was significantly increased in the elastase group compared with controls on Days 7 and 14. Simultaneously, a marked increase in neutrophil infiltration and elastin degradation as well as decrease in smooth muscle integrity were observed in aortic tissue after elastase treatment compared with controls. Moreover, a significant increase in fluorescence intensity of c-FLFLF-Cy7 imaging probe was also observed in elastase-treated mice on Day 7 (approximately twofold increase) and Day 14 (approximately 2.5-fold increase) compared with respective controls. SPECT imaging demonstrated

Tuberculosis: Role of Nuclear Medicine and Molecular Imaging With Potential Impact of Neutrophil-Specific Tracers

“…[ 99m Tc]Tc-cFLFLF was observed to accumulate in aortic tissue treated with elastase when compared to the controls. A marked increase in neutrophil accumulation was observed in aortic tissue, confirming the role of non-invasive molecular imaging to help map out pathophysiology using [ 99m Tc]Tc-cFLFLF (180).…”

Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression

“…PMNs infiltration and activation, and chemokine-mediated neutrophil recruitment contribute to the pathogenesis of AAA and may serve as diagnostic and therapeutic targets [ 88 , 89 , 90 ]. For instance, the chemokine-like factor family with sequence similarity 3, member D (FAM3D), a dual FPR1/FPR2 agonist, is markedly upregulated in human AAA tissues [ 90 ], and cinnamoyl-F-(D)L-F-(D)L-F-K (cFLFLF), a PEGylated peptide ligand that binds FPR1 on activated neutrophils, allows the early, accurate and noninvasive diagnosis of AAA [ 91 ].…”

“…r Cardioprotective role by preserving inotropic responsiveness at the level of ventricular muscle and contractile function of cardiac muscle in vitro[70][71][72][73] FPR1 blockade m Beneficial effects mediated by abrogation of reperfusion-induced exacerbation of infarct size[78] Blood pressure (BP) levels FPR1 C32T (rs5030878) single nuclear polymorphism (SNP) h Negative prognostic factor and detrimental effects associated with increased C-reactive protein (CRP) levels linearly related with BP[83][84][85] Abdominal aortic aneurysm (AAA) FPR1 involvement m Detrimental effects since FPR1 results involved in neutrophil recruitment and aggravated AAA development[91] Acute myocardial infarction (AMI) FPR1 as a differentially expressed gene (DEG) h Role has to be determined even if FPR1 results a DEG in human AMI blood tissue, compared with normal blood tissue using microarray data[75] Potential beneficial role for AMI prevention[76] Platelet-mediated complications FPR1 inhibition or gene deletion m and h Detrimental effects by impairing agonist-induced platelet activation in…”

A fluorescent photoaffinity probe for formyl peptide receptor 1 labelling in living cells

“…6 Imaging of FPR1 is of growing interest for diagnostics. For example a fluorescent FPR1 peptide-based probe was recently used to visualise infiltrating neutrophils during abdominal aortic aneurysm in mice, 7 and imaging revealed the location of granulomas associated with Tuberculosis infection. 8 A greater understanding of the fundamental biology of this receptor (e.g.…”