Capillary Proliferation in Systemic‐Sclerosis‐Related Pulmonary Fibrosis: Association with Pulmonary Hypertension

Abstract

ObjectiveWe sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)‐related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH).MethodsTwo pulmonary pathologists blindly evaluated 360 histologic slides from lungs of 31 SSc‐PF explants or autopsies with (n = 22) and without (n = 9) PH. The presence of abnormal small arteries, veins, and capillaries (pulmonary microcirculation) was semiquantitatively assessed in areas of preserved lung architecture. Capillary proliferation (CP) within the alveolar walls was measured by its distribution, extent (CP % involvement), and maximum number of layers (maximum CP). These measures were then evaluated to determine the strength of their association with right heart catheterization–proven PH.ResultsUsing consensus measures, all measures of CP were significantly associated with PH. Maximum CP had the strongest association with PH (P = 0.013; C statistic 0.869). Maximum CP 2 or more layers and CP % involvement 10% or greater were the optimal thresholds that predicted PH, both with a sensitivity of 56% and specificity of 91%. The CP was typically multifocal rather than focal or diffuse and was associated with a background pattern of usual interstitial pneumonia. There was a significant but weaker relationship between the presence of abnormal small arteries and veins and PH.ConclusionIn the setting of advanced SSc‐PF, the histopathologic feature of the pulmonary microcirculation best associated with PH was capillary proliferation in architecturally preserved lung areas.

Pathogenesis, clinical features, and phenotypes of pulmonary hypertension associated with interstitial lung disease: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative ‐ Group 3 Pulmonary Hypertension

“…In addition, there are changes involving all layers of the vessel wall thus constituting a “panvasculopathy.” Interestingly, the number of capillaries is increased in non‐fibrotic areas and reduced where fibrosis is more prominent 34,35 . This finding is associated with the presence of PH in ILD 36 and has also been observed in systemic sclerosis (SSc)‐related fibrosis with PH 37 . Notably, all the vascular changes, such as hypertrophy and/or hyperplasia of the three arterial wall layers and pulmonary‐bronchial anastomoses, can be found in ILD patients with and without PH but they are generally more pronounced in ILD‐PH patients 12,23 .…”

“… 34 , 35 This finding is associated with the presence of PH in ILD 36 and has also been observed in systemic sclerosis (SSc)‐related fibrosis with PH. 37 Notably, all the vascular changes, such as hypertrophy and/or hyperplasia of the three arterial wall layers and pulmonary‐bronchial anastomoses, can be found in ILD patients with and without PH but they are generally more pronounced in ILD‐PH patients. 12 , 23 While prominently increased vascular wall thickness may be found in arteries, arterioles, and venules in fibrotic areas, non‐fibrotic areas show a pattern characterized by occlusion of pulmonary venules, muscularization of arterioles, and capillary multiplication 38 (Figure 2 ).…”

Lung vascular changes as biomarkers of severity in systemic sclerosis–associated interstitial lung disease

“…These data are in line with our CT evaluation, which found a significant correlation between all kind of vessel numbers and the extent of HC (typical of usual interstitial pneumonia pattern), with only a weak or absent correlation with the GGO (more prominent in non-specific interstitial pneumonia pattern). In addition, the same capillary proliferation parameters were also significantly increased in patients complicated by PAH vs non-PAH cases [24]. Lung vascular changes as biomarkers of severity in SSc-associated ILD…”

“…In SSc patients with ILD_EXT 5%, a significantly higher vessel volume was found, in particular in smaller arteries below 4 mm of diameter. In the pathological slices derived from explanted or autoptic lungs from SSc-ILD, different parameters of capillary proliferation were significantly increased in patients with usual interstitial pneumonia in comparison with those with nonspecific interstitial pneumonia [24]. These data are in line with our CT evaluation, which found a significant correlation between all kind of vessel numbers and the extent of HC (typical of usual interstitial pneumonia pattern), with only a weak or absent correlation with the GGO (more prominent in non-specific interstitial pneumonia pattern).…”

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study

“…[3][4][5][6][7] Lastly, parenteral treprostinil has putative advantages related to pulmonary venodilation and antiangiogenesis. 54 These properties may be of relevance since PH/PF lung pathology often exhibits venopathy and capillary proliferation, 55,56 in addition to the typical arteriopathy of Group I PAH. 57 Nevertheless, as this was not a prospective, controlled trial, the effects of parenteral prostacyclin in patients with PH/PF reported here do not prove efficacy of this agent, although recent data using inhaled prostacyclin appear promising in PH/PF and importantly, included an AI subgroup.…”