Infectious agents, inflammation, and growth factors: how do they interact in the progression or stabilization of mild human atherosclerotic lesions?
Advanced complicated atherosclerotic lesions have been related to many factors, including inflammation, infectious agents, and growth factors. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP), inflammation, and growth factors have been associated with severe atherosclerotic lesions in necropsy material in recent work at our lab. The present study intends to clarify the pathogenesis of atherosclerosis, analyzing which of these elements (macrophages, MP, CP, lymphocytes, and growth factors) are associated with initial development of atherosclerotic lesions, discriminating elements related to stabilization of the plaque versus those related to subendothelial active accumulation of macrophages in living patients. Surgical ascending aorta fragments presenting mild atherosclerotic lesions from 30 coronary atherosclerotic patients were immunohistochemically quantified regarding CP, MP, T cells (CD4, CD8), B cells (CD20), macrophages (CD68), and growth factors [platelet-derived growth factor A (PDGF-A), PDGF-B, transforming growth factor-beta (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Cases were grouped according to the presence or not of active accumulation of macrophages at the subendothelium that indicates atheroma in development: group I (GI) fragments with <4 CD68+ cells/x400 field, in normal distribution (mean 1.8 +/- 1) representing stable atherosclerotic mild lesion, and GII fragments presenting >or=4 CD68+ cells/x400 field, in a non-normal distribution, mean (8.9 +/- 4.8, atheromas in progress), which was followed by increased number of lymphocytes. The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p < 0.001. Percentage area positive for CP antigens was significantly lower in GI than in GII: 1.0 vs. 9.2, p < 0.001. There was a higher percentage area occupied by MP than CP in both GI and GII (7.8 vs. 13.8). There was no difference regarding mean number of growth factor-positive cells/x400 field: PDGF-A, 1.4 vs. 3.9; PDGF-B, 3.4 vs. 5.7; TGF-beta, 0.9 vs. 2.2; and GM-CSF, 2.0 vs. 2.2. Considering all cases, a positive correlation was seen between inflammatory cells and CP+ cells (r > 0.5 and p < 0.01). Growth factors did not correlate with inflammatory cells, CP, or MP and were usually seen in smooth muscle cell and fibrotic areas. Study of initial atherosclerotic lesions showed that MP is present in both kinds of lesion: stable and active subendothelial accumulation of macrophages. Stabilization was related to proportional increase of both infectious agents, which were also related to increased amount of PDGF-A and PDGF-B. Active macrophage accumulation lesions were related to higher elevation in CP concentration at subendothelial regions, in association with B cells, but not of MP and growth factors. MP and CP, inflammation, and growth factors, which were already described in severe atherosclerotic lesions in necropsy material, are also present in mild lesions in living patients, strongly favoring a pathogenetic role for these bacteria in the pathogenesis of atherosclerosis. Predominance of CP in relation to MP may favor progression of the plaque, which is associated with increased B-cell proliferation. PDGF-A and PDGF-B are associated with plaque stability, at least in arterial segments not prone for development of complicated lesions.
Góis
José
J
Heart Institute (InCor), São Paulo, Brazil.
Higuchi
Maria
M
Reis
Márcia
M
Diament
Jayme
J
Sousa
Januário
J
Ramires
José
J
Oliveira
Sérgio
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D018951:Antigens, CD20 / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001013:Aorta, Thoracic / Q000737:chemistry / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D001018:Aortic Diseases / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D001402:B-Lymphocytes / Q000473:pathology; D001706:Biopsy; D016993:Chlamydophila pneumoniae / Q000302:isolation & purification; D016207:Cytokines / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D006090:Gram-Negative Bacteria / Q000302:isolation & purification*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009177:Mycoplasma pneumoniae / Q000302:isolation & purification; D010982:Platelet-Derived Growth Factor / Q000032:analysis; D013601:T-Lymphocytes / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000032:analysis; D000097382:CD68 Molecule
D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C067980:CD68 antigen, human; D000097382:CD68 Molecule