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INVITED REVIEW

HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

Hypoxia, leukocytes, and the pulmonary circulation

Kurt R. Stenmark, Neil J. Davie, John T. Reeves, and Maria G. Frid

Developmental Lung Biology Laboratory, University of Colorado Health Sciences Center, Denver, Colorado

	ABSTRACT

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Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-₁ in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.

monocyte/macrophage; pulmonary hypertension; fibrocyte; neovascularization; vascular remodeling

	EVIDENCE FOR HYPOXIA-INDUCED LEUKOCYTE RECRUITMENT TO TISSUES INCLUDING THE LUNG

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Hypoxia and leukocytes in the systemic circulation.   Leukocytic invasion into ischemic or hypoxic tissues is now well documented. For instance, macrophages represent an important component of the leukocytic infiltrate in a majority of malignant tumors, in some instances comprising up to 50% of the tumor cell mass. These tumor-associated macrophages are thought to originate from peripheral blood monocytes that are recruited into the tumor from the circulation (rather than from resident macrophages present in tissue before the tumor developed). There is good evidence that these macrophages are recruited to the tumor environment specifically via hypoxia-regulated signaling pathways (30, 36, 53). Macrophages are believed to contribute to tumor angiogenesis through the secretion of a variety of proangiogenic factors and to support tumor growth by secreting a number of factors important for proliferation, invasion, and metastasis of tumor and stromal cells (Table 1). Increased numbers of macrophages have also been observed in ischemic areas of dermal wounds, atherosclerotic plaques, synovium of joints with rheumatoid arthritis, and eyes with proliferative retinopathy (7, 9, 14, 22). Wood and colleagues (16, 57) demonstrated in rats that systemic hypoxia induced by breathing 10% O₂ induces increased leukocyte-endothelial interactions within minutes, followed by leukocyte emigration to the perivascular space within 2–4 h. This response is observed in several (mesenteric, remaster, and pial) microcirculation beds, suggesting a generalized response to hypoxia (16, 57). Thus the nascent theme that hypoxia-mediated recruitment of leukocytes is an important contributor to various systemic disease processes raises the question as to whether hypoxia causes leukocytic invasion into the lung.

The effect of acute hypoxia on leukocyte recruitment and cytokine production has also been studied in humans. In patients with high-altitude pulmonary edema (HAPE), increases in the absolute number of cells in bronchoalveolar lavage fluid (BALF), especially neutrophils and macrophages, compared with healthy individuals have been observed (31, 48). In addition, increased levels of TNF-, IL-1, IL-6, and IL-8 have been noted, levels that quickly return to normal on recovery (19, 31, 48). Whether the inflammatory cells directly contribute to the hypoxia-induced edema formation or are a secondary or late phenomenon is currently unclear (5).

Chronic hypoxia and leukocytes in the lung.   Chronic hypoxic exposure, especially in the young, is characterized by the development of striking fibroproliferative changes in the adventitia of both large and small pulmonary arteries (52). These changes have long been assumed to be due to increased proliferation and extracellular matrix protein production by resident pulmonary artery adventitial fibroblasts. However, the cell-restricted nature of this concept has recently been challenged by observations in the systemic circulation showing that circulating mononuclear cells with fibroblast-like properties (termed "fibrocytes") are recruited to sites of tissue injury and participate in the repair process (6, 39, 34, 58, 47). In the lung, Phillips et al. (38) recently showed that circulating mononuclear fibrocytes are the major contributors to lung fibrosis after bleomycin-induced injury. Furthermore, Hashimoto et al. (20) demonstrated the bone marrow origin of fibroblast precursors that contribute to pulmonary fibrosis. With regard to the pulmonary circulation, we recently presented data demonstrating the robust appearance of mononuclear cells in the pulmonary artery adventitia of both infant rats and neonatal calves exposed to chronic hypoxia (15). The time course (24 h–4 wk) analysis showed the early appearance of monocytes in the pulmonary artery adventitia and their continued accumulation over time of hypoxic exposure. We established a nonresident (circulating) origin for these cells. Importantly, the hypoxia-induced accumulation of macrophages appeared to be specific for the pulmonary circulation, because no macrophage recruitment was noted in the systemic circulation (aorta). Furthermore, no neutrophils were identified in the pulmonary perivascular areas at the time points analyzed.

Ex vivo studies in human lung tissue have revealed inflammatory cell infiltrates (macrophages and lymphocytes) in the areas of plexiform lesions in severe chronic pulmonary arterial hypertension, as well as an increased expression of the chemokines, RANTES and fractalkine (13, 45). Collectively, these findings in both animal models and humans provide strong support for the idea that hypoxic exposure induces leukocyte infiltration into the lung and wall of pulmonary arteries where they can have both acute and long-lasting effects on vascular function and structure.

	RECRUITMENT OF MONOCYTES INTO HYPOXIC TISSUES: POTENTIAL MECHANISMS

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A variety of factors are involved in the recruitment of monocytes from the bloodstream to the specific tissue sites. Factors include chemokines, cytokines, and mitogenic peptides (30, 36). Chemokines are known to induce recruitment of monocytes from the bloodstream into tissues. Chemokines are divided into four subclasses (CXC, CC, C, and CX3C), and their specific effects on target cells (monocytes/macrophages) are mediated via members of a family of seven transmembrane G protein-coupled receptors (3, 55). Several CC chemokines, in particular CCL2 (MCP-1) and CCL5 (RANTES), specifically attract and activate monocytes, and these molecules have been most heavily implicated in monocyte recruitment in tumors and other inflammatory disease processes (36). CCL2 and CCL5 are expressed by tumor cells, fibroblasts, and endothelial cells, and their expression has been shown to positively correlate with the number of macrophages, at least in a variety of tumor settings. Furthermore, both CCL2 and CCL5 have been found to stimulate monocytic cell lines, blood monocytes, and tissue macrophages to secrete matrix metalloproteinases, including MMP-9, MMP-19, and µ-PA (42). These proteases degrade basement membranes and extracellular matrix components and appear to aid leukocyte migration into tissues. They have also been implicated in the proteolytic remodeling of the extracellular matrix and in modulating local growth factor availability, which may be important in supporting adventitial fibroblast and/or smooth muscle cell (SMC) activation (27, 40). Importantly, increases in CCL2 (MCP-1) expression have been found in the lung and blood vessels of all animal models of hypoxic exposure described above (33, 35, 60).

Other chemokines may also be involved in monocyte recruitment to the hypoxic vessel wall. Monocytes and macrophages respond to the chemotactic effects of CXCL12 [stromal cell-derived factor-1 (SDF-1)] via the expression of the CXCR4 receptor. In fact, many tissues, including the lung, may constitutively express/secrete CXCL12. However, hypoxia has been shown to significantly upregulate expression of CXCL12/SDF-1 in resident fibroblasts and endothelial cells, and circulating monocytes have been shown to increase their expression of CXCR4 under hypoxic conditions (8, 34, 46).

A number of cytokines have also been implicated in the recruitment of leukocytes into tumors and other hypoxic tissues. Perhaps the most important is the heparin-binding glycoprotein vascular endothelial growth factor (VEGF), whose expression is known to be upregulated under hypoxic conditions. VEGF-A has been clearly shown to be chemotactic for monocytes and macrophages via activation of the VEGFR-1 (Flt-1) receptor by these cells (4, 45). A positive correlation between elevated VEGF expression and the number of infiltrating macrophages has been demonstrated in breast tumors (32). We demonstrated upregulated VEGF-A expression in the pulmonary artery adventitia of chronically hypoxic animals in association with increased neovascularization and monocyte accumulation (12, 15). Thus VEGF, produced locally by a number of different cell types in response to hypoxia, can attract monocytes into the local environment.

Endothelins and TGF- family members may also participate in the recruitment of monocytes to the pulmonary circulation. ETs-1–3 are small vasoactive and mitogenic peptides that are secreted by a wide variety of cell types, including fibroblasts, in response to hypoxia. Like chemokines, endothelins mediate their effects on monocytes by binding to seven transmembrane G protein-coupled receptors (ET-RA and ET-RB) (17). ET-1 is known to be chemotactic for monocytes through a mechanism involving binding to the ET-RA on these cells. ET-2 is a chemoattractant for macrophages by binding the ET-RB (which is not expressed on monocytes so they do not migrate toward ET-2) (10, 17). Numerous investigators have documented increased concentrations of ET-1 in the lung and pulmonary arteries of hypoxic animals (27). TGF- family members are also known to be regulated by hypoxia and to be chemoattractant for monocytes (44). We have preliminary evidence suggesting upregulation of active TGF-₁ in the pulmonary artery adventitia of hypoxic animals, making it another candidate for inducing monocyte recruitment to the hypoxic vessel wall.

Within the pulmonary circulation, one must consider that hypoxia may not be the only stimulus driving the expression of molecules that induce leukocyte recruitment. Exposure to hypoxia elevates pulmonary arterial pressure. Even a modest elevation of lung vascular pressure has been shown to activate proinflammatory responses (such as P-selectin upregulation) in endothelial cells of the lung venular capillaries (28). This response appears to be coupled through reactive oxygen species generated by mitochondria (23). Thus both hypoxia and its attendant hemodynamic effects could participate in leukocyte recruitment.

Because it is clear that the factors involved in leukocyte recruitment may be tissue specific and vary in their sensitivity to hypoxic regulation, a systematic evaluation of the effects of hypoxia, in the presence and absence of hemodynamic changes, on pulmonary vascular cell production of chemokines and cytokines is needed. In addition, the possibility that hypoxia exerts different effects on chemokine and/or adhesion molecule expression in bronchial vs. pulmonary artery endothelial cells also needs to be considered because the bronchial circulation (vasa vasorum) may serve as a major portal of monocyte entry into the hypoxic lung.

	POTENTIAL CONTRIBUTION OF LEUKOCYTES TO ABNORMALITIES IN LUNG VASCULAR TONE AND TO STRUCTURAL REMODELING

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Leukocytes and vascular tone.   Recruitment of leukocytes into the lung airspaces or the vessel wall itself can have significant impact on the function and structure of lung blood vessels. Activated macrophages and/or neutrophils can release a variety of factors including reactive oxygen species (ROS) and proteolytic enzymes capable of directly causing vasoconstriction and increases in vascular permeability (41, 57). It has also been postulated that activated adventitial fibroblasts, through the production of ROS, can act as a "sink" for nitric oxide (NO) produced by the endothelium (41). Thus, under certain circumstances, less NO may be available to the medial SMC, leading indirectly to vasoconstriction. It is possible that activated monocytes/macrophages, accumulating on the outside of the vessel wall, could also, through release of ROS, contribute to abnormalities in tone. Further support for the idea that hypoxia-induced changes in the lung leukocyte recruitment may alter vascular tone comes from observations that TNF-^–/– mice are completely protected against hypoxia-induced increases in pulmonary artery pressure (50).

Leukocytes and vascular structural remodeling.   Monocytes and circulating mononuclear fibrocytes recruited to the pulmonary vessel wall could contribute to the changes in SMC and fibroblast proliferative status and phenotype observed in response to chronic hypoxic exposure (52) through the release of numerous growth factors (Table 1) in a manner similar to their reported effects on stromal cell proliferation and differentiation in tumors (30, 36). It has been reported that hypoxic pulmonary artery adventitial fibroblasts secrete factors, regulated by HIF-1 expression, capable of stimulating vascular SMC proliferation (43). Therefore, the possibility that leukocytes recruited to the hypoxic pulmonary vessel wall in large numbers (15) secrete factors, which trigger the growth and/or migration of resident fibroblasts and SMCs, needs to be considered.

Marked production and accumulation of extracellular matrix proteins, especially type I collagen, is observed in hypoxia-induced vascular remodeling (27, 40, 52). The cells responsible for the matrix protein production have long been assumed to be resident fibroblasts or SMC. The possibility that nonresident cells may contribute to increased matrix protein accumulation within various tissues was raised at least 150 years ago, beginning with the studies of Paget in the 1850s (37). A decade ago, Bucala and colleagues (34, 39, 58) described the subpopulation of circulating leukocytes, which they termed "fibrocytes" that can be recruited from the circulation into wounds and can produce collagen. Since then, many studies have supported the idea that at least some collagen-producing cells in wounds and various injured tissues are derived from circulating mononuclear fibrocytes. The support for the idea that circulating rather than resident cells are critical in collagen production in lung fibrotic responses, comes from observations by Phan's group (20), demonstrating that, in the majority of collagen-producing cells, bleomycin-induced pulmonary fibrosis are the bone marrow-derived fibroblast precursors. Phillips et al. (38) most recently demonstrated that bleomycin-induced pulmonary fibrosis, in fact, is mediated by circulating mononuclear fibrocytes that accumulate within the lung. Our preliminary studies in chronically hypoxic calves and rats demonstrate that collagen-producing cells in the pulmonary artery adventitia express leukocyte/macrophage markers (CD11b, CD14, CD45, CD68/ED1) (15).

The accumulation of myofibroblasts [-smooth muscle (SM)-actin expressing fibroblasts] in the pulmonary artery adventitia of chronically hypoxic animals is well documented, and their presence is speculated to contribute to high pulmonary vascular resistance (49). It has even been suggested that the adventitial myofibroblasts can migrate and incorporate into the media, assume at least some SMC-like characteristics, and contribute to medial thickening (29, 51). Hypoxia can directly induce resident pulmonary artery adventitial fibroblasts to express -SM-actin (49). In addition, it has been shown that circulating fibrocytes can be induced to express -SM-actin by factors including TGF-₁ (34, 39, 58). Thus it is possible that newly appearing myofibroblasts in the adventitia and media of chronically hypoxic animals are derived from nonresident cells. Support for this possibility comes from studies of the bronchial tissue of asthmatic lungs where the appearance of myofibroblasts was shown to be due, at least in part, to the recruitment of circulating fibrocytes (47). Our recent findings in both calves and rats also suggest that chronic hypoxic exposure induces the appearance of cells expressing a macrophage marker CD68/ED1 and -SM-actin in the pulmonary artery adventitia. Thus circulating mononuclear cells/fibrocytes may contribute to the accumulation of collagen-producing cells and myofibroblasts observed in hypoxic forms of pulmonary hypertension.

It is also well known that tissue macrophages and fibrocytes are potent producers of pro-angiogenic factors (Table 1) and thus are important contributors to new blood vessel formation (18, 34, 36, 39). This concept is now well accepted in tumor biology, where macrophages have been shown to play critical roles in tumor angiogenesis (30, 34, 36). The appearance of monocytes in the adventitia of hypoxic animals thus may help explain our previously published finding of marked neovascularization in the adventitia of chronically hypoxic animals (12). One hypothesis is that mononuclear cells/fibrocytes are recruited to the arterial adventitia and stimulate neovascularization, which in turn acts as a conduit for continued delivery of circulating precursor cells. Thus a feedforward loop develops whereby circulating monocytic cells are continuously delivered to the adventitial wall to participate in the remodeling process (Fig. 1).

View larger version (32K): [in this window] [in a new window]   Fig. 1. MCP, monocyte chemoattractant protein; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor; ET, endothelin; TGF, transforming growth factor; PA, pulmonary artery; SMC, smooth muscle cell; ETR, ET receptor; VEGFR, VEGF receptor; ETR, ET receptor.

Studies based on other experimental approaches have also supported the idea that leukocytes are important players in various models of pulmonary hypertension. Kourembanas and colleagues (35, 60) demonstrated that transgenic mice overexpressing hemoxygenase-1 (HO-1) are protected from the development of pulmonary inflammation, as well as pulmonary hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Ikeda et al. (24) demonstrated that a dominant negative inhibitor of CCL2/MCP-1 chemokine significantly reduced the progression of monocrotaline-induced pulmonary hypertension as evaluated by right ventricular systolic pressure and hypertrophy, medial hypertrophy of pulmonary arteries, and mononuclear cell infiltration into the lung (24). Furthermore, gadolinium chloride injections prevented right ventricular hypertrophy and smooth muscle hyperplasia around pulmonary vessels in a neonatal rat model of hyperoxia-induced (60% O₂) pulmonary hypertension (26).

	CONCLUSION

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Experimental data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes may be recruited to the pulmonary circulation in response to both acute and chronic hypoxia and that these cells play an important role in the pulmonary hypertensive process. Early leukocyte recruitment could participate in increasing permeability of the pulmonary and/or bronchial circulation. Early changes in permeability may be an early critical step in the remodeling process. Continued recruitment of monocytes and mononuclear fibrocytes might contribute directly (via differentiation into collagen producing cells and/or myofibroblasts) to structural changes. These cells could also induce phenotypic changes in resident SMC and fibroblasts. They could also stimulate angiogenesis of the vasa vasorum as suggested in atherosclerosis, which, in turn, would provide a conduit for further delivery of leukocytes and progenitor cells. If indeed nonresident cells play a significant role in the vascular remodeling process, new therapeutic options for the treatment of pulmonary hypertension are raised. Understanding the mechanisms of cell recruitment and the pathways used to differentiate into mesenchymal cells will be critical first steps in unraveling the role of these cells in the hypoxic pulmonary hypertensive process.

	GRANTS

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The project was supported by National Heart, Lung, and Blood Institute Grants SCOR 5 P50-HL-57144-08, PPG 5 PO1-HL-14985-32.

	ACKNOWLEDGMENTS

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The authors gratefully acknowledge J. A. Brunetti and D. L. Burke for excellent technical assistance, Dr. I. F. McMurtry for valuable discussion, and M. McGowan and S. E. Hofmeister for help in preparation of this manuscript.

	FOOTNOTES

 

Address for reprint requests and other correspondence: K. R. Stenmark, Univ. of Colorado Health Sciences Center, 4200 E. 9th Ave., Box B131, Denver, CO 80262 (E-mail: kurt.stenmark{at}uchsc.edu)

Deceased 15 September 2004.

	REFERENCES

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1. Aaronson PI, Robertson TP, and Ward JP. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol 132: 107–120, 2002.[CrossRef][Web of Science][Medline]
2. Archer S and Michelakis E. The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O₂ sensors, and controversies. News Physiol Sci 17: 131–137, 2002.[Abstract/Free Full Text]
3. Balkwill F. Chemokine biology in cancer. Semin Immunol 15: 49–55, 2003.[CrossRef][Web of Science][Medline]
4. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, and Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87: 3336–3343, 1996.[Abstract/Free Full Text]
5. Bartsch P, Mairbaurl H, Swenson ER, and Maggiorini M. High altitude pulmonary edema. Swiss Med Wkly 133: 377–384, 2003.[Medline]
6. Bayes-Genis A, Campbell J, Carlson P, Holmes D, and Schwartz R. Macrophages, myofibroblasts and neointimal hyperplasia after coronary artery injury and repair. Atherosclerosis 163: 89–98, 2002.[CrossRef][Web of Science][Medline]
7. Bjornheden T, Levin M, Evaldsson M, and Wiklund O. Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler Thromb Vasc Biol 19: 870–876, 1999.[Abstract/Free Full Text]
8. Ceradini DJ, Kulkarni AR, Callaghan MJ, Teppter OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, and Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine [Advance Online Publication http://www.nature.com/naturemedicine, 2004.]
9. Crowther M, Brown NJ, Bishop ET, and Lewis CE. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol 70: 478–490, 2002.
10. Cui P, Tani K, Kitamura H, Okumura Y, Yano M, Inui D, Tamaki T, Sone S, and Kido H. A novel bioactive 31-amino acid endothelin-1 is a potent chemotactic peptide for human neutrophils and monocytes. J Leukoc Biol 70: 306–312, 2001.[Abstract/Free Full Text]
11. Danenberg HD, Fisbein I, Epstein H, Waltenberger J, Moerman E, Monkkonen J, Gao J, Gathi I, Reichi R, and Golomb G. Systemic depletion of macrophages by liposomal bisphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol 42: 671–679, 2003.[Web of Science][Medline]
12. Davie NJ, Crossno JT, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, and Stenmark KR. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 286: L668–L678, 2004.[Abstract/Free Full Text]
13. Dorfmuller P, Perros F, Balabanian K, and Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 22: 358–363, 2003.[Abstract/Free Full Text]
14. Esser P, Heimann K, and Wiedemann P. Macrophages in proliferative vitreoretinopathy and proliferative diabetic retinopathy: differentiation of subpopulations. Br J Ophthalmol 77: 731–733, 1993.[Abstract/Free Full Text]
15. Frid MG, Brunetti JA, and Stenmark KR. Chronic hypoxia induces the appearance of cells with a dual fibroblast-macrophage phenotype in pulmonary arterial adventitia (Abstract). Am J Resp Crit Care Med 169, Suppl: A400, 2004.
16. Gonzalez NC and Wood JG. Leukocyte-endothelial interactions in environmental hypoxia. Adv Exp Med Biol 502: 39–60, 2001.[Web of Science][Medline]
17. Grant K, Loizidou M, and Taylor I. Endothelin-1: a multifunctional molecule in cancer. Br J Cancer 88: 163–166, 2003.[CrossRef][Web of Science][Medline]
18. Hartlapp I, Abe R, Saeed RW, Peng T, Voelter W, Bucala R, and Metz CN. Fibrocytes induce and angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J 15: 2215–2224, 2001.[Abstract/Free Full Text]
19. Hartmann G, Tschop M, Fischer R, Bidlingmaier C, Riepl R, Tschop K, Hautmann H, Endres S, and Toepher M. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 12: 246–252, 2000.[CrossRef][Web of Science][Medline]
20. Hashimoto N, Jin H, Liu T, Chensue S, and Phan SH. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 113: 243–252, 2004.[CrossRef][Web of Science][Medline]
21. Hoch JR, Stark VK, van Rooijen N, Kim JL, Nutt MP, and Warner TF. Macrophage depletion alters vein graft intimal hyperplasia. Surgery 126: 428–437, 1999.[Web of Science][Medline]
22. Hollander AP, Corke KP, Freemont AJ, and Lewis CE. Expression of hypoxia-inducible factor 1 alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum 44: 1540–1544, 2001.[CrossRef][Web of Science][Medline]
23. Ichimura H, Parthasarathi K, Quadri S, Issekutz AC, and Bhattacharya J. Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. J Clin Invest 111: 691–695, 2003.[CrossRef][Web of Science][Medline]
24. Ikeda Y, Yonemitsu Y, Kataoka C, Kitamoto S, Yamaoka T, Nishida K, Takeshita A, Egashira A, and Sueishis K. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 283: H2021–H2028, 2002.[Abstract/Free Full Text]
25. Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y, Hida T, Oguchi Y, Ambati J, Miller JW, Gragoudas ES, Ng YS, D'Amore PA, Shima DT, and Adamis AP. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198: 483–489, 2003.[Abstract/Free Full Text]
26. Jankov JP, Luo X, Belcastro R, Copland I, Frndova H, Lye SJ, Hoidal JR, Post M, and Transwell AK. Gadolinium chloride inhibits pulmonary macrophage influx and prevents O(2)-induced pulmonary hypertension in the neonatal rat. Pediatr Res 50: 172–183, 2001.[Web of Science][Medline]
27. Jeffery TK and Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45: 173–202, 2002.[CrossRef][Web of Science][Medline]
28. Kuebler WM, Ying X, Singh B, Issekutz AC, and Bhattacharya J. Pressure is proinflammatory in lung venular capillaries. J Clin Invest 104: 495–502, 1999.[Web of Science][Medline]
29. Jones RC and Jacobson M. Angiogenesis in the hypertensive lung: response to ambient oxygen tension. Cell Tissue Res 300: 263–284, 2000.[CrossRef][Web of Science][Medline]
30. Knowles H, Leek R, and Harris AL. Macrophage infiltration and angiogenesis in human malignancy. Cancer Inflammation 256: 189–204, 2004.[CrossRef]
31. Kubo K, Hanaoka M, Yamaguchi S, Hayano T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, and Honda T. Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan. Thorax 51: 739–742, 1996.[Abstract/Free Full Text]
32. Leek RD, Hunt NC, Landers RJ, Lewis CE, Royds JA, and Harris AL. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 190: 430–436, 2000.[CrossRef][Web of Science][Medline]
33. Madjdpour C, Jewell UR, Kneller S, Ziegler U, Schwendener R, Booy C, Klausli L, Pasch T, Schimmer RC, and Beck-Schimmer B. Decreased alveolar oxygen induces lung inflammation. Am J Physiol Lung Cell Mol Physiol 284: L360–L367, 2003.[Abstract/Free Full Text]
34. Metz CN. Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci 60: 1342–1350, 2003.[CrossRef][Web of Science][Medline]
35. Minamino T, Christou H, Hsieh CM, Liu Y, Dhawan V, Abraham NG, Perrella MA, Mitsialis SA, and Kourembanas S. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci USA 98: 8798–8803, 2001.[Abstract/Free Full Text]
36. Murdoch C, Giannoudis A, and Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood [prepublished online July 1, 2004.]
37. Paget J. Lectures On Surgical Pathology. Cambridge: Royal College of Surgeons of England, 1863.
38. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, and Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114: 438–446, 2004.[CrossRef][Web of Science][Medline]
39. Quan TE, Cowper S, Wu SP, Bockenstedt LK, and Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 36: 598–606, 2004.[CrossRef][Web of Science][Medline]
40. Rabinovitch M. Pulmonary vascular remodeling in hypoxic pulmonary hypertension. In: Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms. Norwell, MA: Kluwer Academic, 2004.
41. Rey F and Pagano PJ. The reactive adventitia: fibroblast oxidase in vascular function. Arterioscler Thromb Vasc Biol 22: 1962–1971, 2002.[Abstract/Free Full Text]
42. Robinson SC, Scott KA, and Balkwill FR. Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNA-alpha. Eur J Immunol 32: 404–412, 2002.[CrossRef][Web of Science][Medline]
43. Rose F, Grimminger F, Appel J, Heller M, Pies V, Weissmann N, Fink L, Schmidt S, Krick S, Camenisch G, Gassmann M, Seeger W, and Hanze J. Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: role of hypoxia-inducible transcription factors. FASEB J 16: 1660–1661, 2002.[Abstract/Free Full Text]
44. Sato K, Kawasaki H, Nagayama H, Enomoto M, Morimoto C, Tadokoro K, Juji T, and Takahashi TA. TGF-beta 1 reciprocally controls chemotaxis of human peripheral blood monocyte-derived dendritic cells via chemokine receptors. J Immunol 164: 2285–2295, 2000.[Abstract/Free Full Text]
45. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, and Shibuya M. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97: 785–791, 2001.[Abstract/Free Full Text]
46. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi E, Saccani D, Nebuloni M, Vao L, Mantovani A, Melillo G, and Sica A. Regulation of the chemokines receptor CXCR4 by hypoxia. J Exp Med 198: 1391–1402, 2003.[Abstract/Free Full Text]
47. Schmidt M, Sun G, Stacey MA, Mori L, and Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 170: 380–389, 2003.
48. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ, Henderson WR, and Martin TR. The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 64: 2605–2613, 1988.[Abstract/Free Full Text]
49. Short M, Nemenoff RA, Zawada WM, Stenmark KR, and Das M. Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. Am J Physiol Cell Physiol 286: C416–C425, 2004.[Abstract/Free Full Text]
50. Smith RM, McCarthy J, and Sack MN. TNF-alpha is required for hypoxia-mediated right ventricular hypertrophy. Mol Cell Biochem 219: 139–143, 2001.[CrossRef][Web of Science][Medline]
51. Sobin SS and Chen PC. Ultrastructural changes in the pulmonary arterioles in acute hypoxic pulmonary hypertension in the rat. High Alt Med Biol 1: 311–322, 2000.[CrossRef][Medline]
52. Stenmark KR, Gerasimovskaya E, Nemenoff RA, and Das M. Hypoxic activation of adventitial fibroblasts: role in vascular remodeling. Chest 122: 326S–334S, 2002.[CrossRef][Web of Science][Medline]
53. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, and Sorg C. Macrophages and angiogenesis. J Leukoc Biol 55: 410–422, 1994.[Abstract]
54. van Rooijen N and van Kesteren-Hendrikx E. Clodronate liposomes: perspectives in research and therapeutics. J Liposome Res 12: 81–94, 2002.[CrossRef][Web of Science][Medline]
55. Vicari AP and Caux C. Chemokines in cancer. Cytokine Growth Factor Rev 13: 143–154, 2002.[CrossRef][Web of Science][Medline]
56. Weinberger B, Carbone T, England S, Kleinfeld AM, Hiatt M, and Hegyi T. Effects of perinatal hypoxia on serum unbound free fatty acids and lung inflammatory mediators. Biol Neonate 79: 61–66, 2001.[CrossRef][Web of Science][Medline]
57. Wood JG, Johnson JS, Mattioli LF, and Gonzalez NC. Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats. J Appl Physiol 89: 1561–1568, 2000.[Abstract/Free Full Text]
58. Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, and Tredget EE. Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 82: 1183–1192, 2002.[Web of Science][Medline]
59. Yuan J and Jason X (Editors). Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms. Norwell, MA: Kluwer Academic, 2004.
60. Zampetaki A, Minamino T, Mitsialis SA, and Kourembanas S. Effect of heme oxygenase-1 overexpression in two models of lung inflammation. Exp Biol Med 228: 42–446, 2003.

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