Inflammatory Cytokines Interleukin6 and Interleukin8

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Hypoxia induces the expression of numerous cytokines and growth factors within the vasculature as well as mononuclear phagocytes. Hypoxia induces secretion of platelet activating factor (PAF) and PDGF from endothelial cells as well as macrophages. Both factors stimulate vascular smooth muscle cell and fibroblast proliferation. In addition, inhibition of PAF and PDGF reduced the hypoxia induced IL-6 and IL-8 expression in pulmonary fibroblast and smooth muscle cells (26). Given the large number of upregulated cytokines, it is not surprising that a variety of different factors are responsible for their activation. Hypoxia induces IL-6 transcription through C/EBP-NF-IL-6, while EGR-1 is responsible for PDGF activation (Table 1) (14, 35).

The role of inflammation in pulmonary hypertension has been observed in numerous animal models. Increased inflammation and cytokine production was directly observed in mice exposed to hypoxia. RNA prepared from hypoxic mouse lungs showed elevated levels ofIL-1, IL-6, MIP-2 (functional homologue of human IL-8), and monocyte chemoattractant protein, MCP-1 (19). Interestingly, these levels were reduced in transgenic mice overexpressing lung heme-oxygenase-1, animals which were also protected from developing HPH (19). Furthermore, rats treated with a PAF inhibitor (20) or the 5-lipoxygenase inhibitor MK866, or mice lacking 5-lipoxygenase (32) had decreased pulmonary artery pressures and decreased pulmonary vascular remodeling (characterized with intimal and medial hypertrophy).


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Figure 1. PAP in rats with anti-VEGF and the effect of VEGF on PAP. A: Rats treated with neutralizing anti-VEGF polyclonal antibodies 3 times per week for 3 weeks under chronic hypoxia had an increase in PAP and right ventricular mass when compared with hypoxic rats treated with rat serum. B: Pulmonary vessel remodeling in 3 rats exposed to chronic hypoxia and treated with anti-VEGF rabbit serum (V1, V2, V3). Note the predominance of medial thickening of medium-sized arteries (arrows), with less than 50% medial thickness with respect to total vessel diameter. Focally, control rats (not shown) had thickened vessels as seen in B (panel c (d). Note that the hilar vessels had similar remodeling (f, g). a-g: HE, 200*, h, i: pentachrome, 100*. C: Infusion of rVEGF (at 200 ng/ml) in the pulmonary circulation ex vivo abolished hypoxic-induced vasoconstriction in the isolated perfused lung. The reduction in PAP with VEGF (b) was similar to that seen with normalization of alveolar 02levels (a). The effect of VEGF was almost abolished by the eNOS inhibitor, L-NNAME (100 mM) (c).

4.4. Vascular Endothelial Growth Factor (VEGF)

VEGF, a critical growth and survival factor for endothelial cells, is ideally suited to play a role in the regulation of pulmonary artery remodeling. Produced by lung SMCs, macrophages, and alveolar cells under normoxic conditions,

VEGF is upregulated in chronic hypoxia in an NO-dependent manner (3, 30). Administration of neutralizing VEGF antibodies exacerbated chronic hypoxia-mediated PH (Fig. 1A and B).

Furthermore, exogenous VEGF administered via an adenoviral vector completely attenuated intimai hyperplasia and caused regression of existing hyperplasia (22). When recombinant VEGF is added to isolated perfused rat lungs, rVEGF abolishes the hypoxic-induced vasoconstriction through the production of nitric oxide (NO) (Fig. 1C). Although this is an acute response, overexpression of VEGF could lead to chronic increases in NO and prostacyclin (PGI2) production in the endothelium, which in turn acts to inhibit smooth muscle cell hyperplasia (33).

The critical role of VEGF in maintenance of lung vascular reactivity was highlighted by the findings that chronic hypoxia in combination with a VEGF receptor blocker cause severe pulmonary hypertension associated with endothelial cell proliferation in rats (27). This model has several features in common with human severe pulmonary hypertension, in particular PPH (31). In a setting where phenotypically-altered pulmonary endothelial cells proliferate in a neoplastic-like manner, VEGF may act in a paracrine manner, stimulating the abnormal growth of endothelial cells (31). Indeed, we found that endothelial cells in plexiform lesions exhibit markers of angiogenesis, in particular, VEGF and its receptor II (KDR) (Fig. 2).

Figure 2. VEGF in human PPH. In situ hybridization for VEGF mRNA in PPH lung. A: VEGF mRNA in bronchiolar cells in PPH lung (anti-sense probe, 200"). B: Sense control. C: VEGF mRNA expression in perivascular macrophages (anti-sense probe, 200x). D: VEGF mRNA in bronchiolar cells in normal lung (anti-sense probe, 200x).

Figure 2. VEGF in human PPH. In situ hybridization for VEGF mRNA in PPH lung. A: VEGF mRNA in bronchiolar cells in PPH lung (anti-sense probe, 200"). B: Sense control. C: VEGF mRNA expression in perivascular macrophages (anti-sense probe, 200x). D: VEGF mRNA in bronchiolar cells in normal lung (anti-sense probe, 200x).

4.5. Prostacyclin

Prostacyclin (PGI2), the main cyclooxygenase product in vascular tissue, functions as a vasodilator and inhibitor of smooth muscle cell proliferation. Produced primarily by endothelial cells, PGI2 activates a family of receptors that exert a broad range of biological actions by raising intracellular cAMP levels.

Historically, its role in pulmonary hypertension was evaluated in the belief that a deficiency of vasodilators was the key alteration in lungs of PPH patients. Patients with severe pulmonary hypertension (SPH) were reported to have decreased serum levels of PGI2 and decreased expression of the enzyme responsible for its production (PGI2 synthase) (29). While PGI2 expression may be decreased in patients with SPH, PGI2 levels are increased in chronically hypoxic rats. Using various inhibitors, the enhanced PGI2 production depended on increased sheer forces secondary to the vasoconstriction as opposed to hypoxia per se (2).

Although hypoxia may not directly induce PGI2 synthesis, animals in which PGI2 production has been altered vary in their susceptibility to HPH. PGI2 receptor knockout mice have normal pulmonary artery pressures. Following chronic hypoxic exposure, pulmonary artery pressure is increased and there is enhanced remodeling of pulmonary vesselsas compared with wild type controls (12). Lung-specific overexpression of PGI2 synthase did not result in abnormal resting pulmonary artery pressures but prevented the development of pulmonary hypertension and pulmonary vascular remodeling when the mice were exposed to chronic hypoxia (11).

The therapeutic supplementation of PGI2 has provided further insight into the pathogenesis of pulmonary hypertension. has been shown to improve hemodynamics, exercise tolerance, and prolong survival in PPH subjects. Furthermore, PGI2 has been demonstrated to induce long term reductions in the pulmonary vascular resistance that exceed those of immediate vasodilation, suggesting a role for inhibition of smooth muscle cell proliferation or antiinflammatory effects on endothelial cells (18). Indeed, several of PGI2 analogs have been shown to inhibit smooth muscle cell proliferation (4).

First described as an endothelium-derived relaxing factor, NO exhibited potent vasodilatory effects. Subsequently, it was found to inhibit smooth muscle cell proliferation. The lung expresses three different isoforms of nitric oxide synthase (NOS). While all may affect vessel remodeling, eNOS and iNOS are the major form expressed within the vasculature. The effect of hypoxia of NOS expression has been controversial. There have been reports of both increased and decreased expression of eNOS within patients with chronic pulmonary hypertension. Recently, quantitative RT-PCR from mouse lung tissues demonstrated hypoxemic induction of eNOS and iNOS expression (9).

Although still controversial, most studies using knock out mice demonstrate that NO diminishes the vascular remodeling induced by chronic hypoxia. While eNOS-deficient mice developed normally under normoxic conditions, exposure to chronic hypoxia resulted in fourfold greater proportion of muscularized small arteries (9). Conversely, mice overexpressing eNOS within the lung had an attenuated response to chronic hypoxia (21).

Figure 3. Schematic of growth factors in vascular remodeling. All three layers of the pulmonary vessel are indicated along with the growth factors produced after exposure to chronic hypoxia.

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