Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages

Abstract

Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models. Methods Murine alveolar macrophages were exposed to long and short populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1 α, COX-2, PGE2) were measured. Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production. Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data.

Mineral Fibres and Asbestos Bodies in Human Lung Tissue: A Case Study

“…The difference in size of the ABs located along the fibre and that of the bulbous ABs at the tip of the fibre has never been considered to date. Time-lapse video microscopy of macrophage-asbestos fibre-binding events [62,63] showed that the macrophages try to internalise the long fibres by preferentially starting from their terminations. Consequently, this portion of the fibre is subject to repeated coatings, leading to increased thickness.…”

Asbestos and Intrahepatic Cholangiocarcinoma

“…Thin and long fibers may induce a state of chronic inflammation in target tissues, due to their ability to persist for a very long time in human body. Indeed as macrophages may reach 10-20 µm diameter, fibers longer 20 µm cannot be completely phagocytosed, thus leading to incomplete or 'frustrated' phagocytosis, characterized by the prolonged release of pro-inflammatory cytokines by activated macrophages [9]. Asbestos-induced chronic inflammation may activate multiple signaling cascades involved in cell proliferation and survival, including the epidermal growth factor receptor (EGFR) pathway [10].…”

Designing biomaterials with immunomodulatory properties for tissue engineering and regenerative medicine

“…For example, in one study, gold nanorods were internalized by macrophages at greater levels than nanospheres owing to preferential uptake of the former via micropinocytosis . In a separate study, glass rods were used as a tool to assess shape dependence by incubating rods of varying lengths with macrophages . Short rods were more rapidly taken up than longer rods, but interestingly, the longer rods, while not readily phagocytosed, induced greater levels of the inflammatory signals IL‐1α and TNF‐α .…”

“…In a separate study, glass rods were used as a tool to assess shape dependence by incubating rods of varying lengths with macrophages . Short rods were more rapidly taken up than longer rods, but interestingly, the longer rods, while not readily phagocytosed, induced greater levels of the inflammatory signals IL‐1α and TNF‐α . This inflammatory response was attributed to “frustrated” phagocytic interactions, a phenomenon that occurs when cells are unable to phagocytose larger‐scale objects.…”

“…This inflammatory response was attributed to “frustrated” phagocytic interactions, a phenomenon that occurs when cells are unable to phagocytose larger‐scale objects. This failure results in the production of reactive oxygen species and inflammatory cytokines which ultimately could lead to chronic inflammation and fibrosis . This shape effect might also be important in the context of scaffolds and implants since these constructs are commonly too large for engulfment and often shed long fibers or other geometries upon degradation or wear.…”