Capillary endothelium damage

The neutrophils adhere to the endothelium, block the capillaries and damage the endothelial integrity. Activated neutrophils produce reactive oxygen metabolites and release a variety of cytotoxic proteins, e.g. proteases, lactoferrin, and they also secrete the enzyme myeloperoxidase (MPO) which catalyzes the formation of potent cytotoxic oxidants such as hypochlorous acid (HOC1) from H202 and chloride ions and N- chloramines [172]. 

Animals that survived 14 days had no abnormalities on pathological examination. The investigators pointed out that the presence of pulmonary edema and hemorrhages in the absence of inflammatory cell infiltration suggests that the smoke caused direct injury to the pulmonary capillary endothelium and that the main cause of death was pulmonary damage. They also commented that, because of the agglomeration of the smoke particles and subsequent precipitation of the compound, concentrations as high as those used could not be maintained under operational conditions.9... 

Basophils are another type of granulocytes with numerous granules that stain darkly with basic dyes. They measure 8—10 pm in diameter and make up only about 1% of WBCs. Basophils migrate to injury sites and cross the capillary endothelium to accumulate in the damaged tissue, where they discharge granules that contain histamine (dilates blood vessels) and heparin (prevents clotting). They enhance local inflammation at the sites of injury and other chemicals that attract eosinophils and other basophils to the area of injury. 

In summary, IPF is a complex disorder that appears to occur in response to repetitive injury within the alveolar space that involves both inflammatory and noninflammatory components (Fig. 2). The AFC and adjacent endothelium are the major cells affected and initiate the release of cytokines followed by an intense immune response, which exacerbates alveolar-capillary BM damage. Without a normal BM, cellular communication (leukocyte to nonleukocyte) is altered, driving lung remodeling toward fibrosis. 

Immediate phase (within 1st hour) - direct damage to endothelium of capillaries and to superficial fibroblasts. 

The stimulation of mesangial cells to release and respond to tumor necrosis factor may accelerate the glomerular infiltration of polymorphonuclear leukocytes and monocytes. Indeed, the injection of tumor necrosis factor enhances glomerular damage in some forms of experimental glomerulonephritis [161]. Another important target is the vascular endothelium where an increase in the local production of tumor necrosis factor-a may result in the formation of capillary thrombi. An increase in plasma and urinary levels of two soluble tumor necrosis factor receptors has be found in patients with chronic renal failure [162]. 

The mechanism of action and the injury potential of lipid mediators are still a matter of debate (Figure 4.3). Malik and co-workers recently reviewed the role of cellular and humoral mediators in pulmonary oedema and concluded that few humoral factors act independently to increase capillary permeability and that these mediators might cause pulmonary venoconstriction and raise pulmonary capillary hydrostatic pressure. This concept is in agreement with results of Shasby et al which demonstrated that leukotriene C4 applied directly to an endothelium monolayer did not accelerate albumin transfer across the monolayer. However, because the culture medium was rich in serum proteins (which avidly bind leukotrienes ), one cannot rule out a direct damaging effect to endothelial cells given access of the molecule to the endothelial cell. 

Examination of the developing capillaiy system in high Pb-exposed animals revealed aberrations in the developing capillaiy buds, which were either dilated or lacked apical processes. Electron microscopic examination has revealed capillaiy damage, with vessel walls containing numerous varicosities, the fusion of membranes periodically interrupted, hypertrophied capillaries and endothelial cells, and a few necrotic endothelieil cefis. Lead appears to be concentrated, at least initially, in bredn capillaries in animals exposed to Pb developmentaUy and is localized in the cytoplasm of the capillaiy endothelium cells eifter an intraperitoneal (ip) injection of ra oactive Pb. ... 

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