Sex differences in global and local connectivity of adolescent posttraumatic stress disorder symptoms.

BACKGROUND: Sex differences in youth's posttraumatic stress disorder (PTSD) symptomatology have not been well studied. METHODS: Based on a recently burgeoning theory of psychopathology networks, this study conducted sex comparisons of global and local connectivity of PTSD symptoms in a sample of 868 disaster-exposed adolescents (57.0% girls; a mean age of 13.4 ± 0.8 years) with significant PTSD symptomatology evaluated by the UCLA PTSD Reaction Index for DSM-IV. RESULTS: The results revealed that global connectivity was stronger in girls' network than in boys', and individual symptoms' connectivity and its rankings differed by sex. Intrusive recollections, flashbacks, avoiding activities/people, and detachment were the most strongly connected symptoms in girls, whereas flashbacks, physiological cue reactivity, diminished interest, and foreshortened future were the most strongly connected symptoms in boys. Several symptoms were identified as featuring large connectivity differences across sex. CONCLUSIONS: These findings provide novel insights into sex differential risk and features of youth's PTSD symptomatology. Sex differences reflected in the co-occurrence of PTSD symptoms may merit more consideration in research and clinical practice.

Biliary epithelial senescence and plasticity in acute cellular rejection.

Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.

Contribution of macrophages to intracochlear tissue remodeling responses following cochlear implantation and neural survival.

Introduction: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani; a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. Materials and methods: 10-12-week-old CX3CR1+/GFP Thy1+/YFP mice on C57Bl6 background with normal hearing were fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7-days after starting the diet, 3-channel cochlear implants were implanted ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28- days post-CI for 5 hrs/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10-, 28- or 56-days post-CI were cryosectioned and labeled with antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus and lateral wall for each turn were traced manually to measure region volume. Density of nuclei, CX3CR1+ macrophages, Thy1+ spiral ganglion neuron (SGN) numbers and ratio of volume of α-SMA+ space/volume of scala tympani were calculated. Results: Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea: this response was initially diffuse throughout the cochlea and later localized to the scala tympani of the basal turn by 56-days post-CI. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all timepoints. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. Discussion: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival.

A narrative review of lateral meniscus transplantation with the bridge in slot: technique and outcomes.

Objective: This narrative review aims to detail the indications, technique, and published outcomes of the bridge in slot technique for lateral meniscus allograft transplantation (LMAT) and to serve as a concise reference for orthopaedists looking to incorporate this method into their practice. Background: The menisci are crucial to normal knee function but are commonly injured; partial and subtotal meniscectomy are frequently performed to address meniscal pathology. Following these procedures, a substantial number of patients go on to develop degenerative joint changes accompanied by pain and disability. LMAT is an attractive option for young, active, lateral meniscal-deficient patients who seek pain relief and improved function but who are not yet prepared to undergo arthroplasty. In the properly indicated patient, the bridge in slot technique is a reliable and effective method for LMAT. Methods: Using a narrative style, this review outlines the indications and preoperative assessment for LMAT, the detailed technical steps for the bridge in slot technique, postoperative considerations, and trends in the surgical outcomes literature. The presented technique is consistent with the senior author's clinical experience and with published literature and the discussed outcomes are elicited from a focused review of recent peer-reviewed sources. Conclusions: The bridge in slot technique is a reliable and effective method for LMAT and is supported by the literature. This technique may confidently be used in patients with severe lateral meniscal pathology who are not yet candidates for arthroplasty.

The origin of alveolar macrophages in mouse radiation chimeras.

This investigation attempted to determine whether the primary source of alveolar macrophages is pulmonary or hematopoietic. We have utilized an antigenic marker to identify cells of hematopoietic origin. Mouse chimeras were produced by irradiating C57B6/AF(1) mice (900 R) and then injecting them intravenously with B10D2/AF(1) bone marrow. The donor animal has an antigenic specificity on the H-2 locus, not shared by the recipient. Alveolar macrophages were obtained by repeated lung washings with physiologic saline at 37 degrees C. Cytotoxic tests were done on bone marrow and alveolar macrophages using anti-31 mouse antibody, absorbed rabbit serum as complement, and trypan blue exclusion as a test for viability. Animals were studied at 7, 14, 21, 28, and 35-50 days and 4, 5, 8, and 11 months after irradiation and bone marrow replacement. By 21 days after irradiation, 90% of the animals had greater than 80% replacement of marrow with donor tissue; and white blood cell and alveolar macrophage counts approached normal. At this time and at later intervals the per cent of donor cells in the lung free cell population was not significantly different from the per cent of donor cells in the bone marrow. Similarly, after aerosol particulate exposure, the percentage of marrow cells and alveolar macrophages of donor origin were not significantly different. This immunologic approach suggests that alveolar macrophages in radiation chimeras are entirely of hematopoietic origin.

Statin Drugs Plus Th1 Cytokines Potentiate Apoptosis and Ras Delocalization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-2pos Disease.

A dendritic cell-based, Type 1 Helper T cell (Th1)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-2pos) ductal carcinoma in situ (DCIS). We hypothesized that drugs with low toxicity profiles that target signaling pathways critical for oncogenesis may work in conjunction with vaccine-induced immune effector mechanisms to improve efficacy while minimizing side effects. In this study, a panel of four phenotypically diverse human breast cancer lines were exposed in vitro to the combination of Th1 cytokines Interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α) and lipophilic statins. This combination was shown to potentiate multiple markers of apoptotic cell death. The combination of statin drugs and Th1 cytokines minimized membrane K-Ras localization while maximizing levels in the cytoplasm, suggesting a possible means by which cytokines and statin drugs might cooperate to maximize cell death. A combined therapy was also tested in vivo through an orthotopic murine model using the neu-transgenic TUBO mammary carcinoma line. We showed that the combination of HER-2 peptide-pulsed dendritic cell (DC)-based immunotherapy and simvastatin, but not single agents, significantly suppressed tumor growth. Consistent with a Th1 cytokine-dependent mechanism, parenterally administered recombinant IFN-γ could substitute for DC-based immunotherapy, likewise inhibiting tumor growth when combined with simvastatin. These studies show that statin drugs can amplify a DC-induced effector mechanism to improve anti-tumor activity.

Smoking impairs long-term dust clearance from the lung.

The time for the long-term clearance of dust from human lungs was measured. Three heavy cigarette smokers and nine nonsmokers inhaled a harmless trace amount of magnetic dust, Fe3O4. From periodic measurements with a sensitive magnetic detector of the amount of this dust remaining in the lungs, a clearance curve was determined for each subject. This magnetic tracer method allows clearance to be safely followed for a much longer time than with radioactive tracer methods. The dust clearance in the smokers is considerably slower than in the nonsmokers. After about a year, 50 percent of the dust originally deposited remained in the lungs of the smokers whereas only 10 percent remained in the lungs of the nonsmokers. The smokers therefore retained five times more dust than the nonsmokers. This impaired clearance of Fe3O4 suggests impaired clearance in smokers of other dusts, such as toxic occupational and urban dusts. The higher retention of these dusts may contribute to the higher incidence of lung diseases in smokers.

DSM-5 posttraumatic stress symptom dimensions and health-related quality of life among Chinese earthquake survivors.

It has been well-documented that posttraumatic stress symptoms cause impairments in health-related quality of life (HRQoL). Until now we have little data on how DSM-5 PTSD symptom dimensions relate to different aspects of HRQoL. Clarifying this question would be informative to improve the quality of life of PTSD patients. This study aimed to investigate the effects of dimensions of a well-supported seven-factor model of DSM-5 PTSD symptoms on physical and psychosocial HRQoL. A total of 1063 adult survivors of the 2008 Wenchuan earthquake took part in this study nine years after the disaster. PTSD symptoms were measured by the PTSD Checklist for DSM-5 (PCL-5). HRQoL was measured by the Medical Outcomes Survey Short Form-36 (SF-36). The associations between PTSD symptom dimensions and HRQoL were examined using structural equation models. Dysphoric arousal symptoms were found to significantly relate to physical HRQoL. Other symptom dimensions were not associated with HRQoL. Our findings contribute to the relationship between DSM-5 PTSD and HRQoL, and carry implications for further clinical practice and research on trauma-exposed individuals.

La evidencia previa indica que los síntomas de estrés postraumático causan déficits en la calidad de vida relacionada con la salud (CVRS). Hasta ahora, tenemos pocos datos sobre cómo las dimensiones de los síntomas del TEPT del DSM-5 se relacionan con diferentes aspectos de la CVRS. Aclarar esta pregunta ayudaría a mejorar clínicamente la calidad de vida de los pacientes con TEPT. Este estudio tuvo como objetivo investigar los efectos de las dimensiones de un modelo bien respaldado de siete factores de los síntomas del TEPT según el DSM-5 sobre la CVRS física y psicosocial. En este estudio participaron mil sesenta y tres supervivientes adultos del terremoto de Wenchuan en 2008, nueve años después del desastre. Los síntomas del TEPT se midieron mediante el Lista de Evaluación del TEPT para el DSM-5 (PCL-5), y la CVRS se midió mediante el Cuestionario de Salud en formato abreviado-36 (SF-36). Las asociaciones entre las dimensiones de los síntomas de TEPT y la CVRS se examinaron utilizando modelos de ecuaciones estructurales. Los síntomas de alerta disfórica se relacionaron significativamente con la CVRS física, mientras que las otras dimensiones de síntomas no se relacionaron con la CVRS.Conclusiones: Nuestros hallazgos aportan conocimiento sobre las relaciones entre el TEPT según el DSM-5 y CVRS, y tienen implicaciones para la práctica clínica y la investigación en individuos expuestos al trauma.

Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations: A unique window into the origins of ScZ?

The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and their potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive processes supported by TC-circuits. In the second part of the paper, data from preclinical research as well as human studies will be summarized that have implicated TC-interactions as a crucial target for NMDA-receptor hypofunctioning. Finally, we will compare these neural signatures with current evidence from ScZ-research, suggesting a potential overlap between alterations in TC-circuits as the result of NMDA-R deficits and stage-specific alterations in large-scale networks in ScZ.

Effects of liposome-encapsulated dichloromethylene diphosphonate on macrophage function and endotoxin-induced mortality.

Dichloromethylene diphosphonate (Cl2MDP), encapsulated into liposomes, is known to eliminate splenic and hepatic macrophages. In the present study we investigated the time course of the effects of i.v. injected Cl2MDP-liposomes on macrophage function in rats from 2 h to 14 days postinjection. We further assessed the impact of Cl2MDP-liposomes on endotoxin-induced lethality. Magnetometry was used to measure uptake and distribution of magnetic particles in different organs and to non-invasively monitor cell organelle motion and disappearance of particles in Kupffer cells. Cl2MDP-liposomes administered to rats pre-injected with magnetic particles, resulted in a biphasic impairment of the cell organelle motion after 1 h and 48 h. At 8 h, retained particles started to leave the liver, indicating the begin of an irreversible damage to hepatic macrophages. The released magnetic material was redistributed and taken up primarily by spleen and bone marrow. Pretreatment with Cl2MDP-liposomes for 24 h and 48 h significantly depressed phagocytic capacity for magnetic particles in Kupffer cells. Again, this was compensated by an increased uptake by spleen, lungs, and bone marrow. Interestingly, i.v. administration of endotoxin after pretreatment with Cl2MDP-liposomes resulted in a significant reduction in mortality from 55% to 14%.

Suppressed apoptosis of pre-B cells in bone marrow of pre-leukemic p190bcr/abl transgenic mice.

Mice transgenic for a p190bcr/abl construct develop pre-B cell leukemia/lymphoma, providing a model of Ph+ ALL. To investigate events in tumorigenesis, immunofluorescence labeling, flow cytometry and a short-term culture assay were used to quantitate precursor B cells and their apoptotic rates in bone marrow of p190bcr/abl transgenic mice over a wide age range. Malignancies appeared rapidly at 8-12 weeks of age, followed by slower tumor onset. At 8-12 weeks in normal mice, the apoptotic rate fell among pro-B cells but increased steeply among pre-B cells, while the total number of B lineage cells declined. In contrast, in p190bcr/abl transgenic mice over the same time period, while pro-B cells remained normal in apoptotic rate and number, apoptosis of pre-B cells was markedly inhibited and the number of B lymphocytes increased. At later ages (14-30 weeks), B cell precursors in control mice remained constant in apoptotic activity and number, while in the few surviving transgenic mice B cell populations were expanded. The results reveal characteristic changes in apoptotic activity among B cell precursors in bone marrow during early life, severely perturbed in preleukemic p190bcr/abl transgenic mice by a preferential suppression of pre-B cell apoptosis. p190bcr/abl may thus promote leukemogenesis by permitting aberrant cells generated during early B cell development to evade a normal quality checkpoint and negative selection.

Noninvasive studies of Kupffer cells in situ by magnetometry.

Magnetic iron oxide (gamma-Fe2O3) particles were injected intravenously into four male New Zealand white rabbits. Most of these particles were phagocytized by the Kupffer cells. When the animal was placed in a magnetic field, the particles in the liver became magnetized and aligned. After removal of the external magnetizing field, the particles collectively produced a remanent magnetic field which was measured at the body surface. The strength of this field was proportional to the amount of magnetic particles present in the liver; sequential measurements thus allowed us to describe their disappearance from the liver. After each magnetization, the remanent field rapidly decayed due to particle rotation (relaxation). Since the particles were confined in phagosomes or secondary lysosomes we conclude that movements of these organelles due to cytoplasmic motion caused relaxation. Magnetic particles might therefore serve as probes for cytoplasmic motility of Kupffer cells in situ.

Oxidative metabolism in the alveolar macrophage: analysis by flow cytometry.

We evaluated the reagents dichlorofluorescin (DCFH) and hydroethidine (HE) for use in flow cytometric analysis of the respiratory burst of alveolar macrophages and monocytes. DCFH and HE are non-fluorescent precursors which can be oxidized intracellularly to the fluorescent compounds dichlorofluorescein and ethidium. Alveolar macrophages (AMs) loaded with either DCFH or HE were analyzed after phorbol myristate acetate (PMA) stimulation. The results, expressed as fmol/cell oxidation product (DCF or ethidium) after fluorometric standardization of the flow cytometer, show that both DCFH (273 +/- 48, mean increase over control +/- SE, fmol/cell, N = 9) and HE (416 +/- 54, N = 11) detected the substantial respiratory burst of hamster AMs. Similar results were obtained with normal human AMs. By using multiparameter analyses, the oxidative response of AMs ingesting opsonized fluorescent latex beads was measured in subpopulations ingesting increasing numbers of particles. A graded increase in oxidation of both DCFH and HE was found in response to increasing phagocytosis. Ingestion of fluoresceinated staphylyococcal bacteria caused similar changes in HE-loaded AMs. Inhibition of respiration with antimycin showed that approximately 95% of the increased oxidative metabolism of hamster AMs ingesting opsonized beads or bacteria was mitochondrial. The remaining 5% (10-40 fmol/cell) is membrane-derived oxidative activity quantitatively similar to that measured in assays of extracellular release of H2O2. Monocytes loaded with either DCFH or HE showed substantial increases in fluorescence after PMA stimulation (mean % increase over control +/- SE at 30 min: 464 +/- 104, DCFH, 505 +/- 156, HE). While DCHF is known to measure H2O2, HE is less well characterized. Exposure of cells to an extracellular source of both superoxide anion (O2-) and H2O2, xanthine oxidase-xanthine, resulted in marked oxidation of intracellular HE. Addition of both superoxide dismutase and catalase blocked this oxidation, indicating that HE can detect both O2- and H2O2. These agents can be useful probes for precise analysis of oxidative metabolism during phagocytosis in AMs and other mononuclear phagocytes.

Quantitative recovery of pulmonary intravascular macrophages from sheep lungs.

Pulmonary intravascular macrophages (PIMs) adhere to the endothelium of lung capillaries and sequester circulating particles and pathogens from the blood. Iron oxide (gamma Fe2O3) 5 mg/kg, administered intravenously, specifically labeled PIMs in situ within the living sheep. Attempts to isolate gamma Fe2O3-labeled PIMs using vascular perfusion (VP) procedures yielded few cells. To improve recovery of PIMs, a proteolytic lung digestion (PLD) procedure was developed. Following PLD, gamma Fe2O3-containing PIMs were recovered by magnets and the amount of gamma Fe2O3 present measured by fluxgate magnetometry. Proteolytic lung digestion recovered 34% of the total gamma Fe2O3 in lung samples and yielded 2 x 10(5) PIMs/g lung with 95% viability. In contrast, VP recovered only 3% of the total gamma Fe2O3 in the lung; furthermore, less than 2% of the recovered gamma Fe2O3 was cell associated. Proteolytic lung digestion followed by magnetic separation is an effective way to recover viable sheep PIMs for in vitro study.

Gadolinium induces macrophage apoptosis.

Gadolinium (Gd) suppresses reticuloendothelial functions in vivo by unknown mechanisms. In vitro exposure of rat alveolar macrophages to GdCl3.6H20 caused cell death, as measured by trypan blue permeability, in both dose- and time-dependent fashions. Even a 10-min exposure to Gd caused significant cell death by 24 h. The morphology of Gd-treated cells, pyknosis and karyorrhexis prior to loss of membrane integrity, suggested apoptosis. Upon flow cytometric examination, Gd-treated propidium iodide-excluding cells demonstrated light scatter changes characteristic of apoptotic cells (decreased forward and increased right angle scatter). Gel electrophoresis of DNA from Gd-treated macrophages clearly showed the ladder pattern unique to apoptotic cells. Electron-dense structures containing Gd were observed via electron spectroscopic imaging within phagosomes and also within nuclei (associated with condensed chromatin). Gadolinium, endocytosed by macrophages and distributed to nuclei, causes apoptosis of macrophages in vitro.

New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus.

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

Mechanisms, measurement, and significance of lung macrophage function.

Macrophages exist throughout the body. They have critical roles in the peritoneal cavity, bone marrow, skin, spleen, liver, and elsewhere. Their migratory patterns, phagocytic behavior, immunologic roles, and secretory potential are pivotal to both defense mechanisms and to the pathogenesis of disease. Macrophages have been implicated recently in such diverse disease processes as arthritis, AIDS, and juvenile onset diabetes. It is important to recognize the existence of other lung macrophages besides alveolar macrophages. Macrophages exist in small and large airways above and below the mucus. They may release chemotactic factors and a variety of mediators. They ingest and degrade antigens and are microbicidal. Interstitial macrophages are in direct contact with the extracellular matrix as well as other cells in pulmonary connective tissue such as fibroblasts. Thus, release of mediators or enzymes by interstitial macrophages can have a profound effect. Pulmonary intravascular macrophages are resident cells within the pulmonary capillaries of some species. They avidly remove particles and pathogens from circulating blood and secrete inflammatory mediators. Finally, pleural macrophages are involved in the fate and consequences of inhaled particles, especially fibers. A key attribute of macrophages is motility. Movement is an essential step in phagocytosis. There can be no particle binding or ingestion unless macrophage-particle contact occurs. To what extent and by what mechanisms do alveolar macrophages move on the alveolar epithelium? We have used optical methods as well as magnetometry to describe macrophage motility. Lung macrophages express an array of contractile proteins that are responsible for spreading, migration, phagocytosis, and the controlled intracellular motions of phagosomes and lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Macrophage damage in relation to the pathogenesis of lung diseases.

Pulmonary macrophages are important since their migratory patterns and behavior are often pivotal events in the pathogenesis of pulmonary disease. Alveolar macrophages act to decrease the probability of particle penetration through epithelial barriers, and their phagocytic and lytic potentials provide most of the known bactericadal properties of the lung. Macrophages are also involved in immune responses and in defense against neoplasms. Increased inert or infectious particles stimulate the recruitment of additional macrophages. Most free cells containing particles eventually reach the airways and are quickly carried to the pharynx and swallowed. In addition, evidence has now accumulated that macrophages play a part in the pathogenesis of pulmonary diseases. For example, the ingestion of some particles by macrophages causes a release of lysosomal enzymes into the macrophage cytoplasm. These enzymes may kill the macrophage, and dead or dying macrophages release a substance with attracts fibroblasts that elicit fibrogenic responses. Other toxic particles, such as cigarette smoke, my lead to a release of proteases and other toxic enzymes. All particles are capable of competitive inhibition of phagocytosis in macrophages and many may be cytotoxic and further depress phagocytosis. In addition, connective tissue macrophages may contribute to lung disease by concentrating and storing potent carcinogens or other toxic particles close to a reactive bronchial epithelium for long periods. Thus, even through macrophages serve as a first line of defense for the alveolar surface, they may also be capable of injuring the host while exercising their defensive role.

The respiratory tract and the environment.

The primary determinants of pulmonary disease are environmental. The same thinness and delicacy of the air-blood barrier which allows rapid exchange of oxygen and carbon dioxide also reduce its effectiveness as a barrier to inhaled allergens, carcinogens, toxic particles, and noxious gases, and micro-organisms. Adults breath 10,000 to 20,000 liters of air daily. This volume of air contains potentially hazardous contaminating particles and gases. Future research should explore the diverse physiological mechanisms which prevent the accumulation and deleterious action of inhaled particles and gases. Since most pulmonary diseases are either initiated by or at least aggravated by the inhalagion of particles and gases, the role of environmental factors in the development of respiratory disease is an area worthy of continued support.