Pulmonary alveolar proteinosis - Is host defense awry?

Pulmonary alveolar proteinosis is a rare disorder caused by abundant accumulation of surfactant-derived components in the lungs. The incidence is estimated to be 0.36 case per million population, and the prevalence, 3.70 cases per million. About 500 cases have been recorded in the literature

The role of CD18-mediated adhesion in neutrophil sequestration induced by infusion of activated plasma in rabbits.

Infusion of activated plasma induces neutropenia and sequestration of neutrophils within the microvasculature. This study examined the role of the adhesion glycoprotein complex, CD11/CD18, in this sequestration. Rabbits pretreated with either the anti-CD18 monoclonal antibody (mAb) 60.3 or saline were given infusions of zymosan-activated plasma (ZAP) or saline. The effect of mAb 60.3 on the changes in circulating neutrophil counts, radiolabeled neutrophil kinetics in the lung, and the pulmonary microvascular accumulation of neutrophils induced by ZAP infusion was determined. The data show that pretreatment with mAb 60.3 did not inhibit either the rate of onset or the severity of the neutropenia but prevented the sustained neutropenia. In addition, mAb 60.3 completely prevented the ZAP-induced changes in radiolabeled neutrophil kinetics and largely inhibited the accumulation of neutrophils within the capillaries and the small vessels when evaluated after 15 min of ZAP infusion. We conclude that neutrophil accumulation is a two-step process, the first occurring through a CD18-independent mechanism that may involve a stimulus-induced decrease in neutrophil deformability and acts to slow neutrophil transit through the lung. The second step requires CD18-dependent adhesion and is needed for prolonged accumulation of neutrophils within the pulmonary microvasculature

Pulmonary alveolar proteinosis and macrophage transplantation

Macrophages are highly variable, and their ontogeny and functions depend on the particular organ in which they reside and on any ongoing disease processes. Lung macrophages are critically important to lung function, and knowledge of their ontogeny and phenotypes is rapidly expanding. Lung macrophages are present within the alveolar spaces and in the airway wall and lumen. Airway macrophages represent both alveolar macrophages that are on their way along the mucociliary escalator toward the nasopharynx and other distinct populations of macrophages, which may have their own ontogeny and function. In healthy lungs, the overarching functions of macrophages include serving as a host-defense surveillance system that protects the lungs, modulating (often dampening) inflammatory and immune responses, and monitoring and regulating the surfactant layer, which is critical to maintaining a low surface tension and enabling the opening of alveoli with each breath

Neutrophil rheology and transit through capillaries and sinusoids

In normal lungs, the concentration of neutrophils within the pulmonary capillary blood is about 40–80 times higher than it is within the blood in large vessels (1). This increased concentration, often referred to as the marginated pool, is thought to play an important role in host defense by allowing neutrophils time to sniff the local environment, looking for evidence of organisms or other stimuli that have escaped the initial barriers of host defense. The increased concentration is due to the difference in the pulmonary capillary transit times of neutrophils compared with erythrocytes (RBCs). Whereas RBC and plasma transit times measure 1–2 s, Lien and Wagner have shown that the median transit time of neutrophils is 26 s, with a wide range of 2 to more than 1,200 s (2, 3). Neutrophils are not simply moving more slowly than RBCs; rather, they travel in hops through the highly anastomosing network of pulmonary capillary segments, with pauses followed by rapid travel. These observations suggest that a neutrophil moves rapidly through the larger capillary segments, but when it encounters a narrow one, it stops and requires time to deform. While neutrophils appear to elongate quickly when only small changes in shape are needed to enter a segment, deformation for entry into segments with diameters less than about 5.3 mm requires a delay (4). This deformation time likely accounts for the longer transit times of neutrophils than RBCs and for the formation of the marginated pool. The large contribution of the deformation time to the total transit time points out the importance of the biomechanical properties of neutrophils, particularly their ability to deform, in the flow of these cells through the pulmonary capillary bed on the path from an arteriole to a venule

Activating integrins isn't always "beta" for neutrophil migration!

The lungs possess extraordinary defenses against bacteria and other stimuli. Initial mechanisms of host defense include the very effective mucociliary escalator and the alveolar macrophages,which clearmany stimuli without inducing an inflammatory response and recruitment of circulating leukocytes. When these defenses are overwhelmed, epithelial cells andmacrophages call in help fromoutside the lungs. In response to bacteria, neutrophils are usually first to arrive, and their response is quick, recognizing a need within minutes

Neutrophils in Innate Immunity

Neutrophils are an important component of innate immunity in the lungs. During bacterial pneumonia, neutrophils are recruited from the capillaries of the pulmonary circulation in the gas-exchanging regions of the lungs. This process requires the coordinated activation of many cells within the lungs, including neutrophils and capillary endothelial cells. Cellular activation during innate immune responses is mediated in part by tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1-initiated signaling through their receptors, activation of nuclear factor kappa B (NF-κB) and downstream gene transcription, endothelial cell signaling initiated by neutrophil adherence to intercellular adhesion molecule (ICAM)-1, and binding of leukocyte adhesion molecules to cellular and matrix ligands. These events are essential to effective host defense during pneumonia

CD11/CD18-Dependent and -independent neutrophil emigration in the lungs: How do neutrophils know which route to take?

Neutrophil adhesion to pulmonary microvascular endothelial cells and migration into the distal air spaces of the lungs occur through at least two adhesion pathways: one that requires the leukocyte adhesion complex, CD11/CD18, and one that does not (1–10). Which pathway is selected appears to depend on the stimulus. The role of CD11/CD18 has been primarily established through the use of antibodies to block the function of this molecule. Neutrophil emigration in response to Escherichia coli, E. coli lipopolysaccharide (LPS), Pseudomonas aeruginosa, immunoglobulin (Ig)G immune complexes, interleukin (IL)-1, and phorbol myristate acetate occurs through adhesion pathways that require CD11/CD18 (1–7). In contrast, Streptococcus pneumoniae, Group B Streptococcus, Staphylococcus aureus, hyperoxia, C5a, and hydrochloric acid elicit neutrophil emigration through pathways not inhibited, despite blockade of the CD11/CD18 adhesion complex (1–10). Even when stimuli elicit emigration primarily through CD18-dependent pathways, anti-CD18 antibodies block neutrophil emigration by only 60 to 80%, leaving about 20 to 40% of neutrophils emigrating through CD18-independent pathways. An autopsy report of a child with complete deficiency of CD11/CD18 (leukocyte adhesion deficiency, type I) showed neutrophils and monocytes within the alveoli and small airways (11), suggesting that human neutrophils, as well as those of mice and rats, can use CD11/CD18-independent mechanisms of neutrophil emigration

Myeloid TBK1 signaling contributes to the immune response to influenza

Macrophages provide key elements of the host response to influenza A virus (IAV) infection, including expression of type I IFN and inflammatory cytokines and chemokines. TBK1 (TNF receptor–associated factor family member–associated NF-kB activator–binding kinase 1) contributes to IFN expression and antivira responses in some cell types, but its role in the innate response to IA in vivo is unknown. We hypothesized that macrophage TBK1 contributes to both IFN and non-IFN components of host defense and IAV pathology. We generated myeloid-conditional TBK1 knockout mice and assessed the in vitro and in vivo consequences of IAV infection. Myeloid-specific loss of TBK1 in vivo resulted in less sever host response to IAV, as assessed by decreased mortality, weight loss and hypoxia and less inflammatory changes in BAL fluid relative to wild-type mice despite no differences in viral load. Mice lacking myeloid TBK1 showed less recruitment of CD64 1 SiglecF 2 Ly6C hi inflammatory macrophages, less expression of inflammatory cytokines in the BAL fluid, and less expression of both IFN regulatory factor and NF-kB target genes in the lung. Analysis of sorted alveolar macrophages, inflammatory macrophages, and lung interstitial macrophages revealed that each subpopulation requires TBK1 for distinct components of the response to IAV infection. Our findings define roles for myeloid TBK1 in IAV-induced lung inflammation apart from IFN type I expression and point to myeloid TBK1 as a central and cell type–specific regulator of virus-induced lung damage

Foxp31 regulatory t cell expression of keratinocyte growth factor enhances lung epithelial proliferation

Repair of the lung epithelium after injury is a critical component for resolution; however, the processes necessary to drive epithelial resolution are not clearly defined. Published data demonstrate that Foxp31 regulatory T cells (Tregs) enhance alveolar epithelial proliferation after injury, and Tregs in vitro directly promote type II alveolar epithelial cell (AT2) proliferation, in part by a contactindependent mechanism. Therefore, we sought to determine the contribution of Treg-specific expression of a growth factor that is known to be important in lung repair, keratinocyte growth factor (kgf). The data demonstrate that Tregs express kgf and that Treg-specific expression of kgf regulates alveolar epithelial proliferation during the resolution phase of acute lung injury and in a model of regenerative alveologenesis in vivo. In vitro experiments demonstrate that AT2 cells cocultured with Tregs lacking kgf have decreased rates of proliferation compared with AT2 cells cocultured with wild-type Tregs. Moreover, Tregs isolated from lung tissue and grown in culture express higher levels of two growth factors that are important for lung repair (kgf and amphiregulin) compared with Tregs isolated from splenic tissue. Lastly, Tregs isolated from human lung tissue can be stimulated ex vivo to induce kgf expression. This study reveals mechanisms by which Tregs direct tissuereparative effects during resolution after acute lung injury, further supporting the emerging role of Tregs in tissue repair

Very late antigen-4 in CD18-independent neutrophil emigration during acute bacterial pneumonia in mice

This study tested the hypothesis that very late antigen (VLA)-4 mediates CD18-independent neutrophil emigration into the air-spaces induced by either Streptococcus pneumoniae, a stimulus that induces primarily CD18-independent neutrophil emigration, or Escherichia coli, toward which only 20-30% of the total number of neutrophils emigrate through CD18-independent pathways. In wild-type (WT) mice, VLA-4 expression was less on neutrophils that emigrated into the airspaces than on circulating neutrophils. Vascular cell adhesion molecule-1 (VCAM-1) mRNA, the major endothelial cell ligand for VLA-4, increased more in E. coli than in S. pneumoniae pneumonia. VCAM-1 protein expression was not detected in capillaries, the major site of neutrophil emigration. Neutrophil emigration during E. coli or S. pneumoniae pneumonia was similar in mice given antibodies against both CD18 and VLA-4 compared with mice given the anti-CD18 antibody and a control antibody. However, in hematopoietically reconstituted mice with both WT and CD18-deficient neutrophils in their blood, the migration of CD18-deficient neutrophils in response to S. pneumoniae was slightly but significantly less in animals pretreated with the anti-VLA-4 antibody than in those receiving a control antibody. These data suggest that VLA-4 plays a small role in CD18-independent neutrophil emigration, but the majority of CD18-independent neutrophil emigration induced by bacteria in the lungs occurs through VLA-4-independent mechanisms