Impact of pulmonary vascular volume on mortality in IPF: is it time to reconsider the role of vasculature in disease pathogenesis and progression?

From the authors:

We were pleased to read the letter from E. Puxeddu and co-workers, written in response to our observation that an increased pulmonary vessel volume, derived using quantitative computed tomography (CT) analysis, strongly predicts mortality in patients with idiopathic pulmonary fibrosis (IPF) [1]. E. Puxeddu and his team highlight a selection of studies that have identified pulmonary vascular alterations in IPF, similar to those seen in pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) [2–4]. They suggest that when considered in the light of these previous reports, our findings add support to the idea that vascular alterations might be the first pathological lesion in IPF preceding, and leading to, fibrogenesis.

Linkage between fibrosis and alterations in pulmonary vessel density in IPF is not a new observation. The histopathological evaluation of surgical lung biopsy samples performed by Ebina et al. [2] established that tissue surrounding regions of fibrosis in IPF is characterised by an increase in vessel profusion, whilst the fibrotic tissue itself demonstrates a reduced number of vessels. In line with these findings, fibroblastic foci, a pathological hallmark of IPF [5], have been shown to be relatively avascular [6] yet have a network of capillaries at the base of the lesion. Furthermore, within fibrotic regions of histopathological IPF samples, the normal reduction in vessel profusion with increasing distance from the alveoli spaces has been shown to be disrupted [7].

More recently, in vivo studies in animal models have highlighted the varied effects on pulmonary fibrosis mediated by modifying angiogenic pathways. In a rat model of bleomycin-induced pulmonary fibrosis, vascular endothelial growth factor (VEGF), an angiogenic mediator, was shown to reduce the severity of pulmonary hypertension yet concomitantly to increase the severity of pulmonary fibrosis [8]. In a similar mouse model, an angiostatic chemokine, CXCL11, was found to reduce total lung collagen deposition and overall fibrosis extent on morphometric analysis. However, the reduction in fibrosis, rather than being mediated through effects on pulmonary fibroblasts, was linked to reductions in numbers of pulmonary endothelial cells and the inhibition of angiogenesis [9]. Building on these reports, endostatin, a collagen degradation product that inhibits the VEGF receptor, has been shown to ameliorate bleomycin-induced pulmonary fibrosis possibly by reducing aberrant pulmonary angiogenesis and reducing alveolar epithelial cell apoptosis [10].

Despite the apparent corroboration from these various in vivo models, the translation of animal models of pulmonary fibrosis and vascular proliferation to human IPF studies must be guarded. Similarly, extrapolating relationships between the pulmonary microvasculature and fibrosis at a cellular level to the more macroscopic changes identified using quantitative CT analysis is a large, and possibly unwarranted, step. Nevertheless, dynamic or functional imaging studies may further elucidate the complex interactions that exist between the vessels in the lung and the development of fibrosis.

With regard to the specific suggestion that vascular stresses occurring secondary to either PVOD or PCH may be the first pathological lesion in the IPF lung, as E Puxeddu and colleagues state, it is worth pointing out that fibrous intimal narrowing of vessels is frequently seen on a histopathological analysis of pulmonary fibrosis, and thus adjacent vascular changes could be secondary to, or an epiphenomenon of, the fibrosing process itself. Thus it remains unclear whether vascular proliferation represents a compensatory response to subjacent pulmonary fibrosis, contributes to fibrogenesis, or represents a combination of the two.

Despite our intentional restraint in suggesting hypotheses to explain our observations about pulmonary vascular volume in IPF, the interest our work has generated is encouraging. Whilst exact relationships are elusive, it is becoming increasingly apparent that understanding the complexities of the pulmonary vasculature is an important but neglected field of study in IPF.

Disclosures