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Biomedical subjects

Michael M Frank

Publications and source records attributed to Michael M Frank.

13 recordsLinked to original sources
PubMed2006

Complement levels and activity in the normal and LPS-injured lung.

Complement, a complex protein system, plays an essential role in host defense through bacterial lysis, stimulation of phagocytosis, recruitment of immune cells to infected tissue, and promotion of the inflammatory response. Although complement is most well-characterized in serum, complement activity is also present in the lung. Here we further characterize the complement system in the normal and inflamed lung. By Western blot, C5, C6, and factor I were detected in bronchoalveolar lavage (BAL) at lower levels than in serum, whereas C2 was detected at similar levels in BAL and serum. C4 binding protein (C4BP) was not detectable in BAL. Exposure to lipopolysaccharide (LPS) elevated levels of C1q, factor B, C2, C4, C5, C6, and C3 in human BAL and C3, C5, and factor B in mouse and rat BAL. Message for C1q-B, C1r, C1s, C2, C4, C3, C5, C6, factor B, and factor H, but not C9 or C4BP, was readily detectable by RT-PCR in normal mouse lung. Exposure to LPS enhanced factor B expression, decreased C5 expression, and did not affect C1q-B expression in mouse and rat lung. BAL from rats exposed to LPS had a greater ability to deposit C3b onto bacteria through complement activation than did BAL from control rats. In summary, these data demonstrate that complement levels, expression, and function are altered in acute lung injury and suggest that complement within the lung is regulated to promote opsonization of pathogens and limit potentially harmful inflammation.

Animals↗
PubMed2006

Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.

Excessive complement activation can result in extreme tissue damage and systemic inflammatory responses, similar to innate immune responses rapidly elicited after systemic adenovirus (Ad) injections. To determine if Ad interactions with the complement system impact upon Ad-induced innate immune responses, we injected Ad into complement-deficient, C3-knockout mice (C3-KO) or wild-type mice (WT) and quantitatively compared multiple anti-Ad innate immune responses in both strains of mice. In Ad-treated WT mice, we noted rapid increases in plasma KC levels (1 h post injection), followed by increases in IL-6, IFN-gamma, RANTES, IL-12(p40), IL-5, G-CSF, and GM-CSF and subsequently thrombocytopenia. Conversely, in Ad-treated C3-KO mice, many of these inflammatory responses were significantly blunted, including the avoidance of Ad-induced thrombocytopenia. Global liver transcriptome responses in Ad-treated WT mice were assessed by RT-PCR-validated gene array analysis and were found to be also significantly affected by the lack of complement activity in Ad-treated C3-KO mice. Finally, our results confirmed the ability of high dose Ads to transduce hepatocytes despite a lack of complement activity. In summary, Ad interactions with the mammalian complement system are significant and likely initiate and/or exacerbate many of the inflammatory responses noted after systemic Ad injections.

Adenoviridae↗
PubMed2006

Hereditary angioedema: the clinical syndrome and its management in the United States.

There have been important breakthroughs in the understanding and treatment of hereditary angioedema (HAE). An associated abnormality of the serum protein C1 inhibitor led to purified protein use to end attacks. Consideration of the endocrine functions led to rediscovery of impeded androgen use in disease prophylaxis. Considerations of pathophysiology led to introduction of epsilon aminocaproic and tranexemic acids in prophylaxis and to a resurgence in trials of new therapeutic agents. We have gone from a situation where it was not uncommon for patients to have a severe attack sometime in their lives that led to airway compromise and possible death to a situation where death from disease is highly unusual. Thus HAE is in many ways a success story of modern medicine.

Aminocaproic Acid↗
PubMed2006

Bypassing complement: evolutionary lessons and future implications.

Lectins like mannan-binding protein are part of the innate immune system. They circulate in association with serine proteases. Upon binding oligosaccharides, they activate the complement cascade analogous to the more familiar but evolutionarily more recent classical pathway, which is triggered by antibody binding to antigen. In this issue of the JCI, Selander et al. developed a sensitive and specific ELISA employing Salmonella-specific sugars to assess the activity of the lectin pathway of complement activation (see the related article beginning on page 1425). This more physiologic assay system allowed the investigators to rigorously define the requirements for lectin pathway activation. Furthermore, they uncovered an unsuspected means for this pathway to reach the desired critical step of activation of the opsonin C3. These types of functional assays will eventually replace the more laborious, less physiologic, and less informative approaches currently in use to monitor complement activation.

Animals↗
PubMed2005

Hereditary angioedema.

PURPOSE OF REVIEW: Major advances have been made in understanding the clinical signs and symptoms, the pathophysiology and the treatment of hereditary angioedema. This disease that often begins in childhood is caused by partial absence of the plasma protein C1-inhibitor. At the present time five pharmaceutical companies are planning or conducting clinical trials of a variety of agents to treat acute attacks of this illness. Here we review our current understanding of this illness and the current approaches to treatment. RECENT FINDINGS: This disease is often missed in childhood or confused with other illness. The clinical signs and symptoms are reviewed. The importance of the kinin generating pathway and bradykinin in causing edema has become central to our understanding of pathophysiology. The many new approaches to therapy all appear promising. SUMMARY: Currently we have effective chronic therapy for this disease, although available drugs have real or potential difficulties in use in children. In the future it is likely that effective therapy for acute attacks of disease will become available in the US. It is important to recognize the clinical manifestations of this potentially fatal illness and to understand the therapeutic options.

Androgens↗
PubMed2004

Role of complement receptors 1 and 2 (CD35 and CD21), C3, C4, and C5 in survival by mice of Staphylococcus aureus bacteremia.

Complement-mediated opsonization and phagocytosis of encapsulated serotype 5 Staphylococcus aureus are essential to host defense. We describe the effects of complement depletion and deficiencies of C4, C5, and complement receptors 1 and 2 on mouse survival after intravenous exposure to S aureus. Depletion of complement proteins in C57BL/6 mice with the use of cobra-venom factor decreased survival compared with that of controls after the induction of bacteremia with mucoid (90% mortality), encapsulated (73%), and unencapsulated (59%) S aureus strains. In this model complement is even more important in the control of infection with encapsulated S aureus (80% of clinical isolates) than in the control of infection by unencapsulated strains. C4-deficient mice demonstrated similar mortality from bacteremia caused by encapsulated S aureus compared with controls, suggesting that in the unimmunized animal the alternative complement pathway contributes more to control of bacteremia caused by encapsulated S aureus than the classical complement pathway or mannan-binding lectin pathway. C5-deficient mice (B10.D2-H2(d) H2-T18(c) Hc(0)/oSnJ) showed similar mortality when subjected to bacteremia caused by encapsulated S aureus compared with C5-sufficient (B10.D2-Hc(1) H2(d) H2-T18(c)/nSnJ) mice, suggesting that in this model the anaphylatoxin C5a and the late complement cascade are not critical to survival of bacteremia induced with the use of these strains. However, C5-deficient mice depleted of C3 with the use of cobra-venom factor had 60% decreased survival compared with untreated C5-deficient mice with bacteremia induced by encapsulated S aureus, suggesting that in this model C3 is more critical than C5 in controlling S aureus bacteremia. Complement receptor 1 (CD35) is the primary receptor for the opsonin C3b. Mice deficient in CD35/CD21 showed a 67% decrease in survival compared with normal mice, suggesting that CD35/CD21 is of major importance in the control of S aureus-induced bacteremia.

Animals↗
PubMed2003

C1-esterase inhibitor and a novel peptide inhibitor improve contractile function in reperfused skeletal muscle.

To determine the role of inhibition of complement activation in the contractile function of skeletal muscle ischemia-reperfusion (I/R) injury, the rat extensor digitorum longus (EDL) muscles underwent 3 h ischemia and received human C1-esterase inhibitor (C1-INH, 100 IU/kg), a synthetic C1q A chain peptide with a similar inhibitory effect on activated C1 (peptide, 5 mg/kg), or human serum albumin control. Results showed a significant overall increase in tetanic contractile forces of the reperfused EDL in both C1-INH and peptide groups compared to controls. Maximum improvement occurred with peptide treatment at 120-Hz stimulation, with an increase in force from 38 +/- 4% of normal in controls to 52 +/- 4% in peptide-treated rats. There were no significant differences between C1-INH and peptide groups. Plasma C3 and C4 activities were significantly increased in both treated groups, suggesting inhibition of complement activation. Our results suggest that complement activation is involved in I/R injury, and inhibition of complement activation may therefore represent a potential therapeutic approach to reducing or preventing I/R injury.

Animals↗
PubMed2002

Surfactant protein A enhances the phagocytosis of C1q-coated particles by alveolar macrophages.

Surfactant protein-A (SP-A) plays multiple roles in pulmonary host defense, including stimulating bacterial phagocytosis by innate immune cells. Previously, SP-A was shown to interact with complement protein C1q. Our goal was to further characterize this interaction and elucidate its functional consequences. Radiolabeled SP-A bound solid-phase C1q but not other complement proteins tested. The lectin activity of SP-A was not required for binding to C1q. Because C1q is involved in bacterial clearance but alone does not efficiently enhance the phagocytosis of most bacteria, we hypothesize that SP-A enhances phagocytosis of C1q-coated antigens. SP-A enhanced by sixfold the percentage of rat alveolar macrophages in suspension that phagocytosed C1q-coated fluorescent beads. Furthermore, uptake of C1q-coated beads was enhanced when either beads or alveolar macrophages were preincubated with SP-A. In contrast, SP-A had no significant effect on the uptake of C1q-coated beads by alveolar macrophages adhered to plastic slides. We conclude that SP-A may serve a protective role in the lung by interacting with C1q to enhance the clearance of foreign particles.

Animals↗