Biomedical subjects

F Gigliotti

Publications and source records attributed to F Gigliotti.

At least 19 recordsLinked to original sources

PubMed2001

Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants.

To determine whether Pneumocystis carinii is associated with clinical illness in the competent host, 107 normal, healthy infants were enrolled in a 2-year prospective cohort study in Chile. P. carinii was identified by specific stains and nested--deoxyribonucleic acid (DNA) amplification of the large subunit mitochondrial ribosomal ribonucleic acid gene of P. carinii f. sp. hominis, and seroconversion was assessed by enzyme-linked immunosorbent assay of serum samples drawn every 2 months. P. carinii DNA was identified in nasopharyngeal aspirates obtained during episodes of mild respiratory infection in 24 (32%) of 74 infants from whom specimens were available for testing. Three (12.5%) of those 24 infants versus 0 of 50 infants who tested negative for P. carinii had apnea episodes. Seroconversion developed in 67 (85%) of 79 infants who remained in the study by 20 months of age and occurred in the absence of any symptoms of disease in 14 (20.8%). The study indicates that P. carinii DNA can be frequently detected in healthy infants, and it raises the hypothesis that they may be an infectious reservoir of P. carinii in the community. Further investigation is needed to identify whether P. carinii causes overt respiratory disease in infants.

Carrier State↗

PubMed2001

Identification of Pneumocystis carinii in the lungs of infants dying of sudden infant death syndrome.

BACKGROUND: Recently Pneumocystis carinii has been identified in a significant number of infants diagnosed as having died from sudden infant death syndrome (SIDS) in South America and Europe. METHODS: We examined lung sections of 79 infants who died with a diagnosis of SIDS in Rochester, NY, and Connecticut for the presence of P. carinii. RESULTS: Organisms with a characteristic silver stain appearance for P. carinii were identified in 14% of the lung sections. CONCLUSIONS: These data suggest that a possible link between some cases of SIDS and infection with P. carinii should be further evaluated and that infection of young infants may serve as an important reservoir for human P. carinii.

Disease Reservoirs↗

PubMed2001

Short course directly observed therapy to monitor compliance with antiretroviral therapy in human immunodeficiency virus-infected children.

We report our experience with short course directly observed therapy (DOT) in six human immunodeficiency virus-infected children who had a poor response to their prescribed therapy. Four to 8 days of DOT resulted in a significant drop in the viral load of all six children, demonstrating that short course DOT is an effective way to document poor compliance with antiretroviral therapy.

Administration, Oral↗

PubMed2001

Pulmonary inflammation disrupts surfactant function during Pneumocystis carinii pneumonia.

During Pneumocystis carinii pneumonia (PCP) in mice, the degree of pulmonary inflammation correlates directly with the severity of lung function deficits. Therefore, studies were undertaken to determine whether the host inflammatory response contributes to PCP-related respiratory impairment, at least in part, by disrupting the pulmonary surfactant system. Protein and phospholipid content and surfactant activity were measured in the lavage fluid of infected mice in either the absence or presence of an inflammatory response. At 9 weeks postinfection with P. carinii, nonreconstituted SCID mice exhibited no signs of pulmonary inflammation, respiratory impairment, or surfactant dysfunction. Lavage fluid obtained from these mice had protein/phospholipid (Pr/PL) ratios (64% +/- 4.7%) and minimum surface tension values (4.0 +/- 0.9 mN/m) similar to those of P. carinii-free control mice. However, when infected SCID mice were immunologically reconstituted, an intense inflammatory response ensued. Pr/PL ratios (218% +/- 42%) and minimum surface tension values (27.2 +/- 2.7 mN/m) of the lavage fluid were significantly elevated compared to those of the lavage fluid from infected, nonreconstituted mice (P < 0.05). To examine the specific role of CD8(+) T-cell-mediated inflammation in surfactant dysfunction during PCP, mice with defined T-cell populations were studied. P. carinii-infected, CD4(+)-depleted mice had elevated lavage fluid Pr/PL ratios (126% +/- 20%) and elevated minimum surface tension values (16.3 +/- 1.0 mN/m) compared to normal mice (P < 0.05). However, when infected mice were additionally depleted of CD8(+) cells, Pr/PL ratios were normal and surfactant activity was improved. These findings demonstrate that the surfactant pathology associated with PCP is related to the inflammatory process rather than being a direct effect of P. carinii. Moreover, CD8(+) lymphocytes are involved in the mechanism leading to surfactant dysfunction.

Animals↗

PubMed2001

Assessing inspiratory muscle strength in patients with neurologic and neuromuscular diseases : comparative evaluation of two noninvasive techniques.

STUDY OBJECTIVES: Static mouth pressure during maximal inspiratory efforts is commonly used to evaluate inspiratory muscle strength. However, maximal inspiratory pressure (MIP) presents some potential limitations likely to be overcome by the measure of mouth pressure during a maximal sniff maneuver in patients with respiratory muscle weakness. The aim of the present study was to assess whether mouth pressure during sniff maneuver (Pmosn) is a better index of inspiratory muscle strength than MIP in patients with neurologic and neuromuscular diseases (NNMD) with and without inspiratory muscle weakness. SUBJECTS AND MEASUREMENTS: Both MIP and Pmosn were measured in 30 patients affected by various types of NNMD and in 41 control subjects. Pmosn was measured with a 5-cm latex balloon-catheter system, the balloon being held in the oral cavity with the lips closed. RESULTS: In control subjects, MIP was either similar (in female subjects) or higher (in male subjects) than Pmosn, the variation coefficients for the two tests being similar both in male subjects (19.3% vs 19.1% for MIP and Pmosn, respectively) and in female subjects (27.5% vs 26.2%, respectively). There was no difference in the Pmosn/MIP ratios observed in the different diseases (one-way analysis of variance, F = 0.29, p = 0.91). In control subjects, a significant inverse relationship between Pmosn/MIP ratio and MIP (r = - 0.66, p < 0.00001) was found, ie, the lower the MIP, the higher the Pmosn/MIP ratio, suggesting an increasing difficulty in performing MIP as MIP values decreased. The majority of patients were between the prediction limits of the regression calculated for control subjects. At variance, patients with Duchenne dystrophy and low MIP were under the prediction limits of the regression calculated for control subjects, indicating a lower-than-expected PMOSN. CONCLUSIONS: In patients with NNMD, irrespective of the etiology, we found the following: (1) Pmosn does not overcome the limitations of MIP measurement; (2) the two maneuvers are not interchangeable, but rather complement one another in the assessment of inspiratory muscle strength; (3) Pmosn may underestimate muscle strength as assessed by MIP in patients with NNMD with inspiratory muscle weakness; and (4) in patients with low MIP, the lower-than-expected Pmosn/MIP ratio confirms inspiratory muscle weakness.

Adult↗

PubMed2001

Perception of dyspnea in patients with neuromuscular disease.

BACKGROUND: The perception of dyspnea is not a prominent complaint of resting patients with neuromuscular disease (NMD). To our knowledge, no study has been addressed at evaluating the interrelationships among lung mechanics, respiratory motor output, and the perception of dyspnea in patients with NMD receiving ventilatory stimulation. MATERIAL: Eleven patients with NMD (mean +/- SD age, 44 +/- 11.8 years; 5 men) of different etiology and a group of normal subjects matched for age and sex (control subjects). METHODS: While patients were breathing room air, lung volumes, arterial blood gases, the pattern of breathing (minute ventilation [E], tidal volume [VT], respiratory frequency, inspiratory time), and maximal (less negative) esophageal pressure during a sniff maneuver (Pessn), as an index of inspiratory muscle strength, were measured. Then we evaluated the response to hypercapnic-hyperoxic stimulation (hypercapnic-hyperoxic rebreathing test [RT]) in terms of breathing pattern, inspiratory swing of pleural pressure (Pessw), and inspiratory effort (Pessw[%Pessn]). During the RT, dyspnea was assessed every 30 s using a modified Borg scale (0 to 10). RESULTS: Pulmonary volumes were reduced in seven patients, and PCO(2) was out of proportion to E in four patients. Group Pessn was 42.8 +/- 23.6 cm H(2)O in patients and 107 +/- 20.4 cm H(2)O in control subjects (p < 0.001). Dynamic elastance (Eldyn) [p = 0.0016] and Pessw(%Pessn) [p < 0.0005] were higher in patients. During the RT, Borg/CO(2), Pessw(%Pessn)/CO(2), and Borg/Pessw(%Pessn) were similar in the two groups, while E/CO(2) and VT/CO(2) were lower in patients (p < 0.0002 for both). As a consequence, for unit change in VT (percentage of predicted vital capacity [%VC]), greater changes in Pessw(%Pessn) were associated with greater Borg scores in patients. Baseline Eldyn related to Pessw(%Pessn)/VT(%VC) during hypercapnia (r(2) = 0.85), an index of neuroventilatory coupling of the ventilatory pump (NVC). NVC predicted a good amount of the variability in Borg/E (r(2) = 0.46, p < 0.02). CONCLUSIONS: In this subset of NMD patients during hypercapnic stimulation, a normal inspiratory motor output per unit change in PCO(2) results in a shallow breathing pattern. The consequent impairment of NVC underlies the higher scoring of dyspnea in these patients.

Adult↗

PubMed2000

Molecular characterization of KEX1, a kexin-like protease in mouse Pneumocystis carinii.

Expression screening of a Pneumocystis carinii-infected mouse lung cDNA library with specific monoclonal antibodies (mAbs) led to the identification of a P. carinii cDNA with extensive homology to subtilisin-like proteases, particularly fungal kexins and mammalian prohormone convertases. The 3.1 kb cDNA contains a single open reading frame encoding 1011 amino acids. Structural similarities to fungal kexins in the deduced primary amino acid sequence include a putative proenzyme domain delineated by a consensus autocatalytic cleavage site (Arg-Glu-Lys-Arg), conserved Asp, His, Asn and Ser residues in the putative catalytic domain, a hydrophobic transmembrane spanning domain, and a carboxy-terminal cytoplasmic domain with a conserved tyrosine motif thought to be important for localization of the protease in the endoplasmic reticulum and/or Golgi apparatus. Based on these structural similarities and the classification of P. carinii as a fungus, the protease was named KEX1. Southern blotting of mouse P. carinii chromosomes localized kex1 to a single chromosome of approximately 610 kb. Southern blotting of restriction enzyme digests of genomic DNA from P. carinii-infected mouse lung demonstrated that kex1 is a single copy gene. The function of kexins in other fungi suggests that KEX1 may be involved in the post-translational processing and maturation of other P. carinii proteins.

Amino Acid Sequence↗

PubMed2000

Transmission of Pneumocystis carinii DNA from a patient with P. carinii pneumonia to immunocompetent contact health care workers.

The transmission of Pneumocystis carinii from person to person was studied by detecting P. carinii-specific DNA in prospectively obtained noninvasive deep-nasal-swab samples from a child with a documented P. carinii pneumonia (PCP), his mother, two contact health care workers, and 30 hospital staff members who did not enter the patient's room (controls). Nested-DNA amplification was done by using oligonucleotide primers designed for the gene encoding the mitochondrial large subunit rRNA of rat P. carinii (P. carinii f. sp. carinii) that amplifies all forms of P. carinii and internal primers specific for human P. carinii (f. sp. hominis). P. carinii f. sp. hominis DNA was detected in samples from the patient and all of his contacts versus none of the 30 hospital staff members. The results, as previously shown in murine models of P. carinii pneumonia, document that person-to-person transmission of P. carinii is possible. This observation suggests that immunocompromised patients not on PCP prophylaxis should not enter the room of a patient with PCP, and it also raises the question as to whether healthy contacts can transmit the disease to immunocompromised patients at risk.

Adult↗

PubMed2000

Mechanism of CO(2) retention in patients with neuromuscular disease.

BACKGROUND: In many studies of patients with muscle weakness, chronic hypercapnia has appeared to be out of proportion to the severity of muscle disease, indicating that factors other than muscle weakness are involved in CO(2) retention. In patients with COPD, the unbalanced inspiratory muscle loading-to-strength ratio is thought to trigger the signal for the integrated response that leads to rapid and shallow breathing and eventually to chronic hypercapnia. This mechanism, although postulated, has not yet been assessed in patients with muscular dystrophy. SUBJECTS: Twenty consecutive patients (mean age, 47.6 years; range, 23 to 67 years) were studied: 11 patients with limb-girdle dystrophy, 3 with Duchenne muscular dystrophy, 1 with Charcot-Marie-Tooth syndrome, 1 with Becker muscular dystrophy, 1 with myotonic dystrophy, 1 with facioscapulohumeral dystrophy, and 2 with amyotrophic lateral sclerosis, without any respiratory complaints. Seventeen normal subjects matched for age and sex were studied as a control group. METHODS: Routine spirometry and arterial blood gases, maximal inspiratory and expiratory muscle pressures (MIP and MEP, respectively), and pleural pressure during maximal sniff test (Pplsn), were measured. Mechanical characteristics of the lung were assessed by evaluating lung resistance (RL) and dynamic elastance (Eldyn). Eldyn was assessed as absolute value and as percent of Pplsn; Eldyn (%Pplsn) indicates the elastic load per unit of inspiratory muscle force. Breathing pattern was assessed in terms of time (inspiratory time [TI]; respiratory frequency [Rf]) and volume (tidal volume [VT]) components of the respiratory cycle. RESULTS: A rapid shallow breathing pattern, as indicated by a greater Rf/VT ratio and a lower TI, was found in study patients compared to control subjects. Eldyn was greater in study patients, while MIP, MEP, and Pplsn were lower. PaCO(2) inversely related to VT, TI, and Pplsn (p = 0.012, p = 0.019, and p = 0.002, respectively), whereas it was directly related to Rf, Rf/VT, Eldyn, and Eldyn (%Pplsn) (p < 0.004 to p < 0.0001). Also Eldyn (%Pplsn) inversely related to TI, and the latter positively related to VT. In other words, increase in Eldyn (%Pplsn) was associated with decrease in TI, and the latter was associated with lower VT and greater PaCO(2). Mechanical and breathing pattern variables were introduced in a stepwise multiple regression that selected Eldyn (%Pplsn) (p < 0.0001; r(2) = 0.62) as a unique independent predictor of PaCO(2). CONCLUSIONS: The present study shows that in patients with neuromuscular disease, elastic load and respiratory muscle weakness are responsible for a rapid and shallow breathing pattern leading to chronic CO(2) retention.

Adult↗

PubMed1999

Chest wall kinematics and respiratory muscle action in walking healthy humans.

We studied chest wall kinematics and respiratory muscle action in five untrained healthy men walking on a motor-driven treadmill at 2 and 4 miles/h with constant grade (0%). The chest wall volume (Vcw), assessed by using the ELITE system, was modeled as the sum of the volumes of the lung-apposed rib cage (Vrc,p), diaphragm-apposed rib cage (Vrc,a), and abdomen (Vab). Esophageal and gastric pressures were measured simultaneously. Velocity of shortening (V(di)) and power [Wdi = diaphragm pressure (Pdi) x V(di)] of the diaphragm were also calculated. During walking, the progressive increase in end-inspiratory Vcw (P < 0.05) resulted from an increase in end-inspiratory Vrc,p and Vrc,a (P < 0.01). The progressive decrease (P < 0.05) in end-expiratory Vcw was entirely due to the decrease in end-expiratory Vab (P < 0.01). The increase in Vrc,a was proportionally slightly greater than the increase in Vrc,p, consistent with minimal rib cage distortion (2.5 +/- 0.2% at 4 miles/h). The Vcw end-inspiratory increase and end-expiratory decrease were accounted for by inspiratory rib cage (RCM,i) and abdominal (ABM) muscle action, respectively. The pressure developed by RCM,i and ABM and Pdi progressively increased (P < 0.05) from rest to the highest workload. The increase in V(di), more than the increase in the change in Pdi, accounted for the increase in Wdi. In conclusion, we found that, in walking healthy humans, the increase in ventilatory demand was met by the recruitment of the inspiratory and expiratory reserve volume. ABM action accounted for the expiratory reserve volume recruitment. We have also shown that the diaphragm acts mainly as a flow generator. The rib cage distortion, although measurable, is minimized by the coordinated action of respiratory muscles.

Abdominal Muscles↗

PubMed1999

Chest wall hyperinflation during acute bronchoconstriction in asthma.

The mechanics of the chest wall was studied in seven asthmatic patients before and during histamine-induced bronchoconstriction (B). The volume of the chest wall (VCW) was calculated by three-dimensional tracking of 89 chest wall markers. Pleural (Ppl) and gastric (Pga) pressures were simultaneously recorded. VCW was modeled as the sum of the volumes of the pulmonary-apposed rib cage (VRC,p), diaphragm-apposed rib cage (VRC,a), and abdomen (VAB). During B, hyperinflation was due to the increase in end-expiratory volume of the rib cage (0.63 +/- 0.09 L, p < 0.01), whereas change in VAB was inconsistent (0.09 +/- 0.07 L, NS) because of phasic recruitment of abdominal muscles during expiration. Changes in end-expiratory VRC,p and VRC,a were along the rib cage relaxation configuration, indicating that both compartments shared proportionally the hyperinflation. VRC,p-Ppl plot during B was displaced leftward of the relaxation curve, suggesting persistent activity of rib cage inspiratory muscles throughout expiration. Changes in end-expiratory VCW during B did not relate to changes in FEV(1) or time and volume components of the breathing cycle. We concluded that during B in asthmatic patients: (1) rib cage accounts largely for the volume of hyperinflation, whereas abdominal muscle recruitment during expiration limits the increase in VAB; (2) hyperinflation is influenced by sustained postinspiratory activity of the inspiratory muscles; (3) this pattern of respiratory muscle recruitment seems to minimize volume distortion of the rib cage at end-expiration and to preserve diaphragm length despite hyperinflation.

Abdominal Muscles↗

PubMed1999

Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia.

The clinical severity of Pneumocystis carinii pneumonia (PCP) correlates closely with the appearance of pulmonary markers of inflammation. Therefore, a model system was developed whereby physiological studies could be performed on live mice to determine the extent to which pulmonary inflammation contributes to respiratory impairment during PCP. P. carinii-infected severe combined immunodeficient mice displayed little evidence of pulmonary inflammation and exhibited normal oxygenation and dynamic lung compliance. When comparably infected littermates were immunologically reconstituted, however, an intense immune-mediated inflammatory response was observed that resulted in significant decreases in both lung compliance and oxygenation. As the pneumonia resolved pulmonary function returned toward normal. To begin to define the cell populations contributing to inflammation-associated respiratory impairment during PCP, similar studies were performed in CD4(+) T cell-depleted mice. Mice depleted of both CD4(+) and CD8(+) cells developed infection, but they demonstrated neither abnormal lung compliance nor increased respiratory rate and displayed no markers of lung injury. In contrast, mice depleted of only CD4(+) T cells exhibited severe pulmonary inflammation and injury, decreased oxygenation and lung compliance, and increased respirations. Respiratory compromise was associated with the presence of activated CD8(+) cells and neutrophils in broncho-alveolar lavage fluid. These observations provide direct experimental evidence that the host's response to P. carinii directly impairs pulmonary function and contributes to the pathogenesis of PCP. Furthermore, CD8(+) T cells likely contribute to the respiratory compromise observed during PCP.

Animals↗

PubMed1999

Physiological changes during severe airflow obstruction in chronic obstructive pulmonary disease.

Chronic expiratory flow limitation and hyperinflation are the mechanical hallmarks of chronic obstructive pulmonary disease (COPD). Although carbon dioxide retention is dependent on the severity of airflow limitation, there is considerable variability in the relationships between arterial carbon dioxide tension (Pa,CO2) and forced expiratory volume in one second (FEV1) or total lung resistance (RL). In stable COPD patients with severe airflow obstruction, shallow breathing and inspiratory muscle weakness are the main factors associated with CO2 retention. In stable COPD patients, the diaphragm is less effective than in normal subjects and, with increasing airflow obstruction and hyperinflation, the contribution to the generation of ventilatory pressure of the ribcage inspiratory muscles increased. Abdominal muscles are recruited during expiration in severe COPD patients and the expiratory rise in gastric pressure is directly related to intrinsic positive end-expiratory (alveolar) pressure (PEEPi). During acute bronchoconstriction, COPD patients with severe airflow obstruction recruited the rib cage inspiratory muscles proportionally more than the diaphragm. The associated recruitment of abdominal muscles results in a reduction in abdominal volume at end-expiration and contributes to a significant extent to PEEPi. Dynamic hyperinflation can be overestimated during chronic and acute airway obstruction if abdominal muscle function is not evaluated.

Acute Disease↗

PubMed1998

Molecular characterization of mouse Pneumocystis carinii surface glycoprotein A.

Since the mouse offers an easily manipulated experimental animal model for the study of the immunopathogenesis of pneumonia caused by the opportunist Pneumocystis carinii, we cloned and characterized cDNAs encoding an abundant, immunogenic surface antigen termed glycoprotein A (gpA) from mouse P. carinii. A cDNA library was constructed in bacteriophage lambda gt11 from P. carinii-infected mouse lung poly(A+) RNA. Using a nucleic acid probe derived from a conserved region of the mouse P. carinii gpA structural gene, cDNAs encoding gpA were identified. A composite full-length gpA coding sequence was assembled from two overlapping cDNA clones. A DNA element homologous to the rat P. carinii upstream conserved sequence (UCS) was identified at the 5' end of several of the mouse P. carinii gpA cDNA clones, just upstream of the sequences encoding gpA structural gene isoforms. Using primer extension analysis, two neighboring putative transcriptional start sites were located on UCS-gpA mRNAs approximately 25 and 30 nt, respectively, upstream of the most 5' gpA cDNA clone isolated, suggesting a 5' UCS of 489 or 494 nucleotides in mouse P. carinii gpA. A comparative alignment of the composite mouse P. carinii gpA deduced amino acid sequence with gpA homologs from rat, human and ferret P. carinii demonstrated 156 identical residues, including 46 cysteines, further supporting the hypothesis for conserved secondary structure, as well as function, for gpA from all P. carinii.

Amino Acid Sequence↗

PubMed1998

Antigenic properties of recombinant glycosylated and nonglycosylated Pneumocystis carinii glycoprotein A polypeptides expressed in baculovirus-infected insect cells.

Since a continuous culture system is not yet available for the opportunistic fungal pathogen Pneumocystis carinii, obtaining suitable amounts of purified P. carinii antigens free of mammalian-host lung contaminants is difficult. Hence, production of recombinant antigen possessing epitopes found in native P. carinii antigens is critical for immunological studies. We utilized the baculovirus expression vector system (BEVS) in insect cells to determine whether B-cell epitopes present in the protein core of a native P. carinii surface glycoprotein were conserved in the recombinant polypeptide, and to investigate its glycosylation by insect cells. B-cell epitopes were retained, but the insect cells appeared to hyperglycosylate the recombinant protein.

Animals↗

PubMed1998

Recognition of Pneumocystis carinii antigens by local antibody-secreting cells following resolution of P. carinii pneumonia in mice.

To examine the repertoire of Pneumocystis carinii antigens recognized by antibody-secreting B cells from tracheobronchial lymph nodes isolated immediately following recovery from P. carinii pneumonia, monoclonal antibodies (MAbs) were produced from these cells. In contrast to previous studies of systemic immunity, P. carinii gpA was not the immunodominant antigen recognized by these B cells. Forty-nine (91%) of 54 P. carinii-specific hybridoma culture supernatants reacted with P. carinii antigens other than gpA. Many of the resulting MAbs recognized a previously uncharacterized antigen expressed on the surface of both cysts and trophozoites. Western blotting using one of the cloned MAbs revealed reactivity with a broad range of antigenic material, with the most intense reactivity in the 50- to 65-kDa region of the blot. The antigens identified by these MAbs merit further investigation regarding protective immunity to P. carinii because they were recognized by B cells in the context of recovery from P. carinii pneumonia.

Animals↗

PubMed1998

Immunization with Pneumocystis carinii gpA is immunogenic but not protective in a mouse model of P. carinii pneumonia.

Immunization with whole Pneumocystis carinii has been shown to protect mice from the development of P. carinii pneumonia (PCP) when they are subsequently immunosuppressed and challenged with viable organisms. To determine whether these results could be duplicated by using a subunit vaccine, we examined the immunogenicity and efficacy of an immunization strategy based on P. carinii gpA. This antigen was chosen for study because passive immunoprophylaxis, based on gpA, has been shown to be partially protective in various animal models of infection. Immunization with gpA produced an anti-gpA specific antibody response comparable to that resulting from immunization with whole organisms. However, in contrast to immunization with whole P. carinii, which was protective, immunization with gpA did not protect T-cell-depleted mice from the development of PCP. These studies suggest that other antigens in addition to gpA need to be evaluated for their role in protective immunity against P. carinii.

Animals↗

PubMed1998

Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia.

Pneumocystis carinii is an important pulmonary pathogen responsible for morbidity and mortality in patients with AIDS. The acute-phase response (APR), the primary mechanism used by the body to restore homeostasis following infection, is characterized by increased levels of circulating fibrinogen (FBG). Although the liver is the primary site of increased FBG synthesis during the APR, we unexpectedly discovered that FBG is synthesized and secreted by lung alveolar epithelial cells in vitro during an inflammatory stimulus. Therefore, we sought to determine whether lung epithelial cells produce FBG in vivo using animal models of P. carinii pneumonia (PCP). Inflammation was noted by an influx of macrophages to P. carinii-infected alveoli. Northern hybridization revealed that gamma-FBG mRNA increased two- to fivefold in P. carinii-infected lung tissue, while RNA in situ hybridization demonstrated increased levels of gamma-FBG mRNA in the lung epithelium. Immunoelectron microscopy detected lung epithelial cell-specific production of FBG, suggesting induction of a localized inflammatory response resembling the APR. A systemic APR was confirmed by a two- to fivefold upregulation of the levels of hepatic gamma-FBG mRNA in animals with PCP, resulting in a corresponding increase in levels of FBG in plasma. Furthermore, immunoelectron microscopy revealed the presence of FBG at the junction of cell membranes of trophic forms of P. carinii organisms aggregated along the alveolar epithelium. These results implicate FBG in the pathogenesis of PCP in a manner similar to that of the adhesive glycoproteins fibronectin and vitronectin, which are known to participate in intra-alveolar aggregation of organisms and adherence of P. carinii to the lung epithelium.

Acute-Phase Reaction↗