Endoneurial Homeostasis

5.1. The Controlled Variables of Endoneurial Homeostasis

5.2. Endoneurial Homeostasis During Development

The various compartments of the nervous system employ homeo-static mechanisms to regulate their respective internal environments. The relevant physiological functional unit for a vertebrate peripheral nerve is a fasciculus, the cylindrical structural entity encompassing axons, glial cells, and other attendant satellite cells that is defined by the perineurium. The physical limit of the perineurium is also a physiological barrier, limiting the exchange of material between the endoneurial space and the general extracellular space surrounding a peripheral nerve.

The specialized microenvironment of peripheral nerve fibers is maintained with the assistance of the BNI. Regulated blood-nerve exchange across the BNI and turnover of endoneurial fluid by convective fluid flow are vital for the maintenance of endoneurial physiological parameters, including blood flow, O2 tension, pH, oncotic pressure, hydrostatic pressure, ion concentrations, within the normal range necessary for the proper functioning of nerve fibers. There are independent transendothelial pathways for the movement of ions and macromolecules. Some of these physiological parameters have been measured: PS to (14C) sucrose (70, 71), (14C) glucose (49), (125I) albumin (34), and 22Na (30); endoneurial blood flow (72, 73); EHP (74, 75); and ion concentration in endoneurial fluid (58, 76). Other parameters have been described only qualitatively or not at all: endoneurial concentration of H+ and Ca2+; rate of convective EFF; volume of endoneurial extracellular space; perineurial permeability to macromolecules; and tortuosity of the endoneurial extracellular contents. The above list of variables is neither exhaustive nor does it relate to all the pathophysiological alterations associated with the endoneurial microenvironment. However, it is hoped that discussions of these few variables with available data during development, nerve degeneration, and regeneration and in a few clinical scenarios will emphasize the relevance of considering pathophysiological alterations as perturbations of endoneurial homeostasis.

During normal development, results from studies employing morphological tracers indicate that the BNB of juvenile animals is more permeable to macromolecules than that of adult animals (23). The decrease in the PS of the BNB during development has been quantified with radiotracer studies (77). An intriguing issue arising out of these observations is how developing nerve with its highly permeable BNB avoids the pathology observed in an adult nerve with a comparably permeable BNI. For example, in the adult elevating the PS of the BNI to an extent where there is extravasation of plasma proteins inevitably leads to endoneurial edema and increased EHP. The primary event is the increase of endoneurial albumin content, which elevates the oncotic pressure in the endoneurial interstitial space. Due to the operation of Starling forces, water is drawn into the endoneurial interstitium from the vascular compartment, leading to elevated endoneurial water content and, together with the low hydraulic conductivity and compliance of the perineurium, causes an increase in the EHP. Elevated EHP can compromise the intrafascicular microcirculation leading to ischemia and its accompanying pathology.

By contrast, a highly permeable BNB during the first weeks of development does not lead to an elevated EHP and edema because the endoneurial accumulation of fluids and osmolytes is prevented by a more permeable perineurium allowing for the clearance of this material by the epineurial lymphatics. Additionally, a higher compliance of the juvenile endoneurial tissue mass could also counter a tendency for an increased EHP. Therefore, in the developing nerve two independent factors contribute to a much more permeable endoneurial microvasculature. The first is the need for a greater blood-nerve exchange of material to support the more active metabolism, and the second is a consequence of tight junction dissolution and reformation during endothelial proliferation in vasculogenesis. Increased permeability of the endoneurial microvasculature does not lead to pathological consequences due to the combination of a relatively more permeable perineurium and epineurial lymphatics, as well as metabolic clearance of plasma-derived macromolecules.

5.3. Endoneurial Homeostasis in Nerve

Degeneration and

Regeneration

Wallerian degeneration is probably the most drastic reorganization of the endoneurial architecture (78, 79). The fact that perineurial permeability increases only about twofold under these conditions (80) argues against a "breakdown" of the barrier properties of this structure. An alternative and more plausible interpretation is a dynamic response of the perineurium to maintain endoneurial homeostasis. Morphologically, perineurial cells in degenerating nerve show no evidence of disruption (81, 82). On the contrary, they proliferate, hypertrophy and increase their organelle content (81).

During Wallerian degeneration, the perineurium exhibits a bimodal increase in permeability (Fig. 3). The initial peak of perineurial permeability, lasting only a few days (80), is most likely related to the acute inflammatory response triggered by the trauma of nerve section, and the proliferative response of the perineurium (81).

TIME (WEEKS)

Fig. 3. Relative changes in perineurial permeability to 22Na, endoneurial volume and perineurial area during Wallerian degeneration is shown. Perin. perm. Perineurial permeability; Endon. volume Endoneurial volume; and Perin. area Perineurial area (reproduced with permission (80)).

TIME (WEEKS)

Fig. 3. Relative changes in perineurial permeability to 22Na, endoneurial volume and perineurial area during Wallerian degeneration is shown. Perin. perm. Perineurial permeability; Endon. volume Endoneurial volume; and Perin. area Perineurial area (reproduced with permission (80)).

Sectioned degenerating nerves show an increased number of mast cells (61, 81, 82), which on degranulation release histamine, a biogenic amine with potent inflammatory properties. The later, sustained increase of perineurial permeability is probably a component of endoneurial homeostasis related to preventing elevation of EHP, and clearing myelin debris from the endoneurium (Fig. 4). The increased permeability of both components of the BNB is likely to facilitate the entry of monocytes into the endoneurium for myelin phagocytosis (83). Lipid droplets and proteinaceous material are present among perineurial layers in degenerating nerves, the cells themselves are not disrupted (81, 82).

Delineation of the properties of the BNB during nerve regeneration provides a more comprehensive picture. From day 4 up to the eighth week after the crush lesion, BNB PS to 22Na was significantly greater than the normal value. The increased ability of

22Na to move into the endoneurial space is compared with the measured endoneurial water content at the same time points in Figs. 5 and 6. However, by the 18th week after the crush, PS was not significantly different from the normal value.

The endoneurial water content, calculated as the wet weight to dry weight ratio increased from day 4 and remained elevated during the entire experimental period (Fig. 6). Its peak at the second week postcrush corresponds to a period of increased PS of the BNB to 22Na. On the other hand, at 18 weeks post crush when the BNB PS to 22Na is normal, the nerve is still edematous.

While an increased BNB PS to plasma macromolecules could elevate the osmolality of the endoneurial fluid and thus draw

TIME (DAYS)

Fig. 4. Endoneurial hydrostatic pressure and perineurial permeability to 22Na during the first 4 weeks of Wallerian degeneration is shown (reproduced with permission (80)).

TIME (DAYS)

Fig. 4. Endoneurial hydrostatic pressure and perineurial permeability to 22Na during the first 4 weeks of Wallerian degeneration is shown (reproduced with permission (80)).

TIME (WEEKS)

Fig. 5. Blood-nerve barrier permeability to 22Na during regeneration after a crush lesion is shown. Time after the lesion is represented in the x-axis. There were four animals at the day 4 and 1 week time points, and five animals at all other time points (Weerasuriya, unpublished data).

TIME (WEEKS)

Fig. 5. Blood-nerve barrier permeability to 22Na during regeneration after a crush lesion is shown. Time after the lesion is represented in the x-axis. There were four animals at the day 4 and 1 week time points, and five animals at all other time points (Weerasuriya, unpublished data).

water into this space, it is contended that a decrease in the endoneurial fluid turnover is also a factor in maintaining the increased water content of the regenerated nerve. On the other hand, the elevated water content is not associated with nerve edema; at 12 weeks after a crush injury the EHP of the regenerating nerve returns to normal (84). It is postulated that an altered compliance of the regenerated nerve helps to maintain EHP in the normal range.

TIME (WEEKS)

Fig. 6. Changes in endoneurial wet weight to dry weight ratio in desheathed rat sciatic nerve following a crush injury is shown. Data are presented as mean ± SEM. The SEMs of normal, and 6, 8, and 18 weeks are smaller than the size of the symbol (Weerasuriya, unpublished data).

TIME (WEEKS)

Fig. 6. Changes in endoneurial wet weight to dry weight ratio in desheathed rat sciatic nerve following a crush injury is shown. Data are presented as mean ± SEM. The SEMs of normal, and 6, 8, and 18 weeks are smaller than the size of the symbol (Weerasuriya, unpublished data).

5.4. Endoneurial The major effects of lead on peripheral nerve are endoneurial

Homeostasis in Lead edema, nuclear inclusion bodies, demyelination, elevation of Neuropathy EHP, and increased permeability of BNB (85). Of these altera tions, the nuclear inclusion bodies are observed first followed by endoneurial edema. It had been suggested earlier (85, 86) that an increase in the permeability of endoneurial capillaries was the primary pathological event leading to subsequent Schwann cell damage and segmental demyelination. Later studies indicated that accumulation of lead in the endoneurium and nerve edema, precede qualitative changes in the permeability of endoneurial capillaries (87, 88). The BNB index to albumin (a measure of the rate of albumin entry and removal from the endoneurium) starts to increase only at 6 weeks in lead-intoxicated rats, and suggests that the change in BNB permeability is subsequent to the direct toxic effect of lead on Schwann cells (89). A subsequent study (90) provided clear, quantitative evidence that endoneurial pathology precedes an increase in permeability of BNB, and furthermore, that the increase in permeability is about threefold. It is further implied that the increase of BNB permeability is not a consequence of disruption of its barrier properties, but more in the nature of an adaptive response to aid in the clearing of myelin debris from the endoneurium. A scheme, which is an extension of earlier hypotheses, attempts to delineate the causal relationships among the changes in various components of the endoneurium in lead-induced neuropathy (Fig. 7). The hypothesis underlying this scheme and its implications are described in detail elsewhere (65).

Fig. 7. Proposed sequence of events leading to demyelination and endoneurial edema in lead neuropathy are shown (reproduced with permission from (65)).

An intriguing but unresolved clinical issue is that lead toxicity predominantly leads to an encephalopathy in children, whereas in adults the major manifestation is a neuropathy. A greater vulnerability of the juvenile cerebral neurovascular unit to Pb is a likely but, as yet, unproven hypothesis.

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