Elevated Basic Fibroblast Growth Factor Levels in Patients With Pulmonary Arterial Hypertension

doi:10.1378/chest.126.4.1255

Chest

Volume 126, Issue 4, October 2004, Pages 1255-1261

https://doi.org/10.1378/chest.126.4.1255 Get rights and content

Study objectives:

Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation.

Design:

Case-control study.

Setting:

Multicenter, tertiary care hospitals.

Participants:

We studied 117 patients with PAH and 60 control subjects.

Measurements:

We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay.

Results:

Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects.

Conclusion:

Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.

Section snippets

Study Population

We studied a cohort of 117 patients with PAH (Table 1). The study was approved by the institutional review committee of the participating centers, and the patients gave informed consent. The control population consisted of 60 normal volunteers (median age, 37.5 ± 10.2 years [± SD]; female gender, 62%) from the participating centers without known cardiopulmonary disease or malignancy. Diagnosis of PAH was established by World Health Organization (WHO) criteria.⁸ Other causes of pulmonary

Urine bFGF Levels

The results of the growth factor levels by etiology of PAH are summarized in Table 2. Patients with PAH had significant elevations in median urine bFGF compared to control subjects (2,305 pg/L vs 1,111 pg/L, p ≤ 0.0001). There was a difference in median urine bFGF level according to etiology of PAH: primary pulmonary hypertension (PPH), 2,741 pg/L; congenital heart disease (CHD), 2,330 pg/L; connective tissue disease (CTD), 1,493 pg/L; p = 0.15 (Fig 1). Significant pairwise comparisons in urine

Discussion

The role of bFGF in PAH has been studied in animal models of pulmonary hypertension. Increased endogenous vascular elastase activity has been shown to occur in experimental models of PAH, and is associated with increases in bFGF production in the lung.⁹ As a result of elastase activity on the extracellular matrix, liberation of matrix-bound mitogens, including bFGF, occurs. bFGF levels increase progressively in airway, vascular, and gas exchange regions of monocrotaline-treated rat lungs.¹⁰

ACKNOWLEDGMENT

We would like to acknowledge Elizabeth Allred, MSc, for statistical support, Susan Connors for technical support, and Dr. D. Langleben for patient samples and critical review.

References (18)

AP Fishman
Clinical classification of pulmonary hypertension
Clin Chest Med
(2001)
RN Channick et al.
New and experimental therapies for pulmonary hypertension
Clin Chest Med
(2001)
J Folkman
Clinical applications of research on angiogenesis
N Engl J Med
(1995)
J Folkman
Angiogenesis in cancer, vascular, rheumatoid and other disease
Nat Med
(1995)
RM Tuder et al.
Histopathology of pulmonary hypertension
Chest
(1998)
GG Pietra et al.
Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute Primary Pulmonary Hypertension Registry
Circulation
(1989)
RM Tuder et al.
Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis
J Pathol
(2001)
M Klagsburn et al.
Vascular endothelial growth factor and its receptors
Cytokine Growth Factors Rev
(1996)
I Vlodavsky et al.
Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix
Proc Natl Acad Sci U S A
(1987)

There are more references available in the full text version of this article.

Cited by (75)

Pulmonary arterial hypertension nanotherapeutics: New pharmacological targets and drug delivery strategies
2024, Journal of Controlled Release
Pulmonary arterial hypertension (PAH) is a rare, serious, and incurable disease characterized by high lung pressure. PAH-approved drugs based on conventional pathways are still not exhibiting favorable therapeutic outcomes. Drawbacks like short half-lives, toxicity, and teratogenicity hamper effectiveness, clinical conventionality, and long-term safety. Hence, approaches like repurposing drugs targeting various and new pharmacological cascades and/or loaded in non-toxic/efficient nanocarrier systems are being investigated lately. This review summarizes the status of conventional, repurposed, either in vitro, in vivo, and/or in clinical trials of PAH treatment. In-depth description, discussion, and classification of the new pharmacological targets and nanomedicine strategies with a description of all the nanocarriers that showed promising efficiency in delivering drugs are discussed. Ultimately, an illustration of the different nucleic acids tailored and nanoencapsulated within different types of nanocarriers to restore the pathways affected by this disease is presented.
FGF/FGFR signaling: From lung development to respiratory diseases
2021, Cytokine and Growth Factor Reviews
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling system regulates a variety of biological processes, including embryogenesis, angiogenesis, wound repair, tissue homeostasis, and cancer. It exerts these regulatory functions by controlling proliferation, differentiation, migration, survival, and metabolism of target cells. The morphological structure of the lung is a complex tree-like network for effective oxygen exchange, and the airway terminates in the middle and distal ends of many alveoli. FGF/FGFR signaling plays an important role in the pathophysiology of lung development and pathogenesis of various human respiratory diseases. Here, we mainly review recent advances in FGF/FGFR signaling during human lung development and respiratory diseases, including lung cancer, acute lung injury (ALI), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.
Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats
2018, Vascular Pharmacology
Citation Excerpt :
However, long-term prognosis of PAH treatment remains poor [13,39]. Role of mitogen-activated protein kinase (MAPK) pathway in pathogenesis of PAH has been documented [31,46], which involves upstream signaling from various receptor tyrosine kinases (TK) such as platelet-derived growth factor receptor beta (PDGFR-β) [4,46,55], fibroblast growth factor receptor (FGFR)-1 [5,53,57], endothelial growth factor receptor (EGFR) [9], and C-Kit receptor [14,40]. Imatinib, a TK inhibitor, reverses pulmonary and myocardial remodeling in the rodent models [8,12,46] and significantly improves right ventricular (RV) functions in the PAH patients [21,47,50] and the Phase III Imatinib in Pulmonary Arterial Hypertension, A Randomized, Efficacy Study (IMPRES) [24].
High-dose imatinib reverses cardiopulmonary remodeling but adverse effects limit its clinical use. Efficacy of the multi-kinase inhibitor sunitinib remains questionable. We compared anti-remodeling effects of imatinib with sunitinib on monocrotaline-induced right ventricular (RV) hypertrophy and pulmonary arterial remodeling in rats, focusing on a lower dose. Fourteen days after monocrotaline injection, oral gavage of imatinib (5, 15, or 50 mg/kg), sunitinib (0.3, 1, 3, or 10 mg/kg), or water for 14 days was started. RV hypertrophy and b-type natriuretic peptide mRNA levels were significantly and dose-dependently reduced, much greater in imatinib- than sunitinib-treated groups. Imatinib normalized muscularization of 20–50 μm intra-acinar pulmonary arteries more significantly than sunitinib. At transcript levels, sunitinib significantly upregulated pulmonary nestin, and downregulated platelet-derived growth factor receptor beta (PDGFR-β), fibroblast growth factor receptor 1, vascular endothelial growth factor receptor-2 and vascular endothelial growth factor (VEGF)-A, but not Raf-1 proto-oncogene serine/threonine kinase mRNAs. Sunitinib also suppressed VEGF-A, but not phosphorylated extra-cellular-signal-related kinase (ERK)-1/2 protein expression. The sole PDGFR-β antagonism of imatinib resulted in significant Raf-1 mRNA and phosphorylated ERK-1/2 protein downregulation, suggesting that the equivocal reversal effect of sunitinib may be due to its VEGF signaling inhibition in the lung. Imatinib's greater dose-dependent reversal on cardiopulmonary remodeling may make a low dose suitable for PAH treatment.
Role of fibroblast growth factors in organ regeneration and repair
2016, Seminars in Cell and Developmental Biology
In its broad sense, regeneration refers to the renewal of lost cells, tissues or organs as part of the normal life cycle (skin, hair, endometrium etc.) or as part of an adaptive mechanism that organisms have developed throughout evolution. For example, worms, starfish and amphibians have developed remarkable regenerative capabilities allowing them to voluntarily shed body parts, in a process called autotomy, only to replace the lost parts afterwards. The bizarre myth of the fireproof homicidal salamander that can survive fire and poison apple trees has persisted until the 20th century. Salamanders possess one of the most robust regenerative machineries in vertebrates and attempting to draw lessons from limb regeneration in these animals and extrapolate the knowledge to mammals is a never-ending endeavor.
Fibroblast growth factors are potent morphogens and mitogens that are highly conserved among the animal kingdom. These growth factors play key roles in organogenesis during embryonic development as well as homeostatic balance during postnatal life. In this review, we provide a summary about the current knowledge regarding the involvement of fibroblast growth factor signaling in organ regeneration and repair. We also shed light on the use of these growth factors in previous and current clinical trials in a wide array of human diseases.
Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension
2023, Arteriosclerosis, Thrombosis, and Vascular Biology
The Anti-Inflammatory Effects and Clinical Potential of Dexmedetomidine in Pulmonary Arterial Hypertension
2023, Journal of Pharmacology and Experimental Therapeutics

View all citing articles on Scopus

This study was supported by a grant to Children's Hospital from EntreMed Inc., and by research grants to Dr. Benisty from the Pulmonary Hypertension Association (PHA/AHA-0020609H), and the Heart and Stroke Foundation of Canada/Canadian Institutes of Health Research.

Dr. Benisty is a scholar of the Clinical Science Program at Harvard Medical School supported by a National Institutes of Health (National Heart, Lung, and Blood Institute) K30 grant (HL-04095).

View full text

Chest

Clinical InvestigationsPULMONARY HYPERTENSIONElevated Basic Fibroblast Growth Factor Levels in Patients With Pulmonary Arterial Hypertension

Study objectives:

Design:

Setting:

Participants:

Measurements:

Results:

Conclusion:

Section snippets

Study Population

Urine bFGF Levels

Discussion

ACKNOWLEDGMENT

Clin Chest Med

Clin Chest Med

Clinical applications of research on angiogenesis

N Engl J Med

Angiogenesis in cancer, vascular, rheumatoid and other disease

Nat Med

Histopathology of pulmonary hypertension

Chest

Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute Primary Pulmonary Hypertension Registry

Circulation

Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis

J Pathol

Vascular endothelial growth factor and its receptors

Cytokine Growth Factors Rev

Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix

Proc Natl Acad Sci U S A

Clinical Investigations
PULMONARY HYPERTENSION
Elevated Basic Fibroblast Growth Factor Levels in Patients With Pulmonary Arterial Hypertension