Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-ß, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

Conceptualizing the Risks of Coronary Heart Disease and Heart Failure Among People Aging with HIV: Sex-Specific Considerations.

Cardiovascular disease (CVD) is emerging as a major threat to healthy aging among people with HIV (PHIV). PHIV face heightened risks for coronary heart disease (CHD)/myocardial infarction (MI) and heart failure (HF), fueled by systemic immune activation and by metabolic dysregulation. Women with HIV (WHIV) evidence unique patterns of vascular and myocardial pathology as compared to men with HIV (MHIV). These patterns include a predilection to microvascular dysfunction and type II MI, as well as a penchant for diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). Investigations are underway to understand how advanced reproductive aging among WHIV influences systemic immune activation and metabolic dysregulation en route to these CVD phenotypes. A key goal is to identify targeted CVD prevention strategies relevant to WHIV, particularly as efficacious treatment approaches to type II MI and HFpEF are lacking.