Tumor-related thrombotic pulmonary microangiopathy: review of pathologic findings and pathophysiologic mechanisms.

We report a middle-aged woman who died 2 days after presenting with dyspnea and severe pulmonary hypertension of unknown etiology. Her symptoms were highly suggestive of pulmonary embolism, but clinical evaluations for that disease yielded negative results. Autopsy revealed a Krukenberg tumor of the left ovary, representing metastatic gastric carcinoma from an occult primary lesion. Although the lungs exhibited no gross evidence of pulmonary emboli or neoplasia, microscopic examination revealed diffuse microscopic metastases in the pulmonary arterial vasculature. The pulmonary arteries exhibited fibrocellular intimal proliferation with smooth muscle colonization of the luminal neoplastic lesions and associated microthrombi. This disease entity, known as tumor-related thrombotic pulmonary microangiopathy, results in generalized microvascular obliteration and subsequent pulmonary hypertension. It is a rare condition that is distinct from ordinary pulmonary thromboembolism and primary pulmonary hypertension. Tumor-related thrombotic pulmonary microangiopathy should be considered diagnostically by the autopsy pathologist in cases of rapidly evolving pulmonary hypertension in a middle-aged or elderly individual, or respiratory failure of unknown cause, especially if there is a history of a visceral malignancy.

Ligand-induced formation of p55 and p75 tumor necrosis factor receptor heterocomplexes on intact cells.

The p55 and p75 tumor necrosis factor receptors are known to mediate their effects on cells through distinct signaling pathways. Under certain circumstances, the two classes of TNF receptors cooperate with each another to produce enhanced cellular responses. The only molecular mechanism proposed thus far to explain this effect is the process of "ligand passing," whereby TNF is concentrated at cell surfaces by binding to p75 and then following dissociation from this receptor class binds with high efficiency to p55. Using the in vivo model of TNF-induced TNF receptor shedding we have uncovered a novel ligand-dependent interaction of the two TNF receptors that occurs upon exposure of cells to TNF. Using TNF receptor-specific monoclonal antibodies that bind TNF receptors in the presence or absence of ligand, we report that TNF induces the formation of heterocomplexes consisting of both p55 and p75 TNF receptors. Whereas immunoprecipitates from untreated or human TNF-treated cells formed with either p55 or p75 TNF receptor-specific monoclonal antibodies contained only the relevant TNF receptor class, anti-p55 or anti-p75 precipitated both receptor types from murine TNF-treated cells. Ligand-induced complex formation was transient, occurred at physiologically relevant concentrations of TNF, and occurred with receptors lacking intracellular domains or that contained irrelevant transmembrane domains. Formation of TNF receptor heterocomplexes may therefore 1) define a novel molecular mechanism of ligand passing and/or 2) contribute to cooperative TNF receptor signaling via the juxtaposition of the intracellular domains of the two receptor classes and the signaling proteins that they recruit.

Constitutive shedding of both p55 and p75 murine TNF receptors in vivo.

Recently, we reported the generation and characterization of hamster mAbs specific for the murine p55 and p75 TNF receptors. Upon characterizing these mAbs in vivo, we discovered that administration of TNF receptor-specific mAb to normal mice resulted in the linear accumulation of the appropriate class of soluble TNF receptor in the circulation. The mechanism underlying soluble receptor accumulation was found to be due to an abrogation of the clearance of constitutively shed soluble receptor by receptor-specific mAb. Levels of p55 or p75 accumulated in the presence of nonblocking, nonagonistic TNF receptor mAb were capable of inhibiting murine TNF-induced responses in vivo. These results document that both p55 and p75 are constitutively shed in substantial amounts in vivo and suggest that the process of constitutive TNF receptor shedding plays an important role in regulating TNF activity under physiologic conditions.

Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: identification of a novel in vivo role for p75.

Monoclonal antibodies (mAbs) specific for the murine p55 and p75 tumor necrosis factor (TNF) receptors were produced after immunization of Armenian hamsters with the purified soluble extracellular domains of each receptor protein. Four p55- (55R) and five p75 (TR75)-reactive mAbs immunoprecipitated the appropriate receptor from the surface of L929 cells. None of the mAbs cross-reacted with the other TNF receptor form. The mAbs were functionally characterized by their ability to inhibit ligand binding and influence TNF-dependent L cell cytolytic activity or proliferation of the murine cytolytic T cell clone CT6. One p55-specific mAb, 55R-593, displayed agonist activity, while two other p55-specific mAbs (55R-170 and -176) were found to be TNF antagonists. The fourth mAb (55R-286) had no functional effects on cells. Several antibodies specific for the p75 TNF receptor partially inhibited recombinant murine TNF-alpha-dependent cytolytic activity (60%). Blocking mAbs specific for p75 but not anti-p55 inhibited TNF-mediated proliferation of CT6 T cells. When used in vivo, p55- but not p75-specific mAbs protected mice from lethal endotoxin shock and blocked development of a protective response against Listeria monocytogenes infection. In contrast, both p55 and p75 mAbs individually blocked development of skin necrosis in mice treated with murine TNF-alpha. These data thus demonstrate the utility of the two families of murine TNF receptor-specific mAbs and identify a novel function of the p75 TNF receptor in vivo.