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(Chest. 2005;128:583S-584S.)
© 2005 American College of Chest Physicians

Circulating Mononuclear Cells With a Dual, Macrophage-Fibroblast Phenotype Contribute Robustly to Hypoxia-Induced Pulmonary Adventitial Remodeling*

Maria G. Frid, PhD; Jacqueline A. Brunetti, BS; Danielle L. Burke, BS; Todd C. Carpenter, MD; Neil J. Davie, PhD and Kurt R. Stenmark, MD

* From the University of Colorado Health Sciences Center, Developmental Lung Biology Research Laboratory, Denver, CO.

Correspondence to: Maria G. Frid, PhD, University of Colorado Health Sciences Center, Developmental Lung Biology Research Laboratory, 4200 E Ninth Ave, Denver, CO 80262; e-mail: Maria.Frid{at}UCHSC.edu

Chronic hypoxic pulmonary hypertension, especially in the young, is characterized by striking fibroproliferative changes in the adventitia of both large and small pulmonary arteries. These changes are thought to contribute significantly to high pulmonary vascular resistance and, in some instances, to cor pulmonale. It has long been assumed that the resident pulmonary artery fibroblasts are the primary contributors to adventitial thickening and fibrosis. However, there is evidence that circulating mononuclear cells of a myeloid origin, which have the capability of exhibiting fibroblast-like properties, can be chemotactically recruited to sites of tissue injury and participate in the repair process.1 In fact, bone marrow-derived fibroblast precursor cells have recently been suggested2 to be major contributors to lung fibrosis following bleomycin-induced injury. However, whether circulating precursor cells with the potential to exhibit fibroblast-like properties contribute to adventitial thickening under hypoxic conditions is unknown. We recently demonstrated3 the presence of hematopoietic precursor cells expressing cKit marker in the adventitia of chronically hypoxic animals. We therefore tested the hypothesis that, in hypoxia-induced pulmonary hypertension, circulating mononuclear cells contribute to pulmonary artery adventitial thickening and fibrosis.

The cellular composition of pulmonary arteries of control and chronically hypoxic hypertensive neonatal calves and young rats was assessed for the expression of leukocyte/macrophage markers (ie, CD45, CD11b, CD14, CD68, and MHCII). Cells in the pulmonary artery adventitia of control animals did not express these markers, whereas in the pulmonary arteries of animals with hypoxia-induced pulmonary hypertension > 50% of adventitial cells expressed leukocyte/monocyte markers. Our assumption that these were blood-borne cells was supported by experiments on rats with hypoxia-induced pulmonary hypertension, in which in vivo 1-1'-dioctodecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-labeled circulating monocytes/macrophages were identified in pulmonary artery adventitial lesions. A nonresident origin of these cells was further supported by organ and primary cell culture experiments in which hypoxia failed to induce the expression of leukocyte markers in resident pulmonary artery fibroblasts of control animals. Notably, double-label immunostaining and confocal microscopy analysis demonstrated that, in animals with hypoxia-induced pulmonary hypertension, most of the macrophage-like cells in pulmonary artery adventitia coexpressed a fibroblast marker, procollagen I, and thus exhibited a dual, macrophage-fibroblast phenotype. In addition, some cells coexpressed macrophage markers and {alpha}-smooth muscle actin, which raises the possibility that some myofibroblasts in the adventitia originate from the circulation. Furthermore, in vitro experiments showed that, compared to controls, cultured peripheral blood mononuclear cells from animals with hypoxia-induced pulmonary hypertension adhered in greater numbers, acquired fibroblast-like morphology, and secreted collagen I and extra-domian-A fibronectin, and some expressed {alpha}-smooth muscle actin.

The observation that circulating mononuclear cells contribute robustly to hypoxic pulmonary adventitial thickening and fibrosis might have profound implications for understanding the pathogenesis of pulmonary hypertension and the future development of therapeutic approaches.


   Footnotes
 
This work was supported by Specialized Center for Research grants No. 5-P50 HL57144–08 and Program Project Grant No. 2 P01 HL014985–31.


   References
TOP
 References
 

  1. Quan, TE, Cowper, S, Wu, S-P, et al (2004) Circulating fibrocytes: collagen-secreting cells of the peripheral blood. J Biochem Cell Biol 36,598-606
  2. Hashimoto, N, Jin, H, Liu, T, et al Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004;113,243-252[CrossRef][ISI][Medline]
  3. Davie, NJ, Crossno, JT, Frid, MG, et al Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 2004;286,L668-L678[Abstract/Free Full Text]



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