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Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by abnormal accumulation of surfactant-associated phospholipoproteinaceous material in the pulmonary alveoli. The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of "bat-wing configuration" and "crazy paving" appearance in high-resolution computed tomography are suggestive, but not diagnostic of PAP. The current gold standard of PAP diagnosis involves histopathological examination of alveolar specimens obtained from bronchoalveolar lavage and transbronchial lung biopsy. The characteristic histopathological features are intraalveolar periodic acid Schiff (PAS)-positive eosinophilic homogeneous material with well-preserved architecture ofalveolar septa. The current standard medical treatment of PAP involves the physical removal of the surfactant-associated phospholipoproteinaceous alveolar deposit by whole lung lavage, which causes clinical and radiological improvement in a majority of patients. Some patients have been successfully treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF).

Objective: Megaloblastosis (i.e., megaloblastic transformation of erythroid precursor cells in the bone marrow) is the cytomorphological hallmark of megaloblastic anemia resulting from vitamin B₁₂ and folate deficiency. It is characterized by a finely stippled lacy pattern of nuclear chromatin, which is believed to be an expression of deranged cellular DNA synthesis. However, the molecular basis of these cytomorphological aberrations still remains obscure. The current presentation describes the results of our studies on some molecular events associated with the development of megaloblastosis. Methods: Transmission electron microscopy was used to study megaloblasts as well as DNA fibers extracted from megaloblastic and normoblastic bone marrows with and without treatment with proteinase K during the extraction procedure; cellular DNA synthesis in bone marrow cultures was studied by incorporation of ³H-thymidine and deoxyuridine suppression test, while histone biosynthesis in bone marrow cells was studied by in vitro incorporation of ³H-tryptophan, ³H-lysine and ³H-arginine into histones. Results: Derangement of DNA synthesis occurred due to an impaired de novo pathway of thymidylate synthesis in both vitamin-B₁₂- and folate-deficient human megaloblastic bone marrows as well as in the bone marrows of rhesus monkeys and rats with experimentally induced folate deficiency. Interestingly, folate-deficient monkeys developed frank megaloblastic bone marrows, but folate-deficient rats did not. On the other hand, megaloblastic changes in the bone marrow of human patients with myelodysplastic syndrome and erythroleukemia were not associated with this DNA synthetic abnormality. Biosynthesis of predominantly arginine-rich histones in megaloblastic bone marrows was markedly reduced as compared to normoblastic bone marrows, which was consistently associated with elongation and despiralization of chromosomes and finely stippled nuclear chromatin in megaloblasts. Conclusion: The impaired biosynthesis of predominantly arginine-rich nuclear histones appeared to be a common molecular event (a denominator) underlying the development of megaloblastosis with or without abnormal DNA synthesis.

An initial effect of carbon nanoparticle (CN) lung exposure is the cellular release of damage‐associated molecular pattern recognition molecules (DAMPs). One of the earliest is the high mobility group box 1 (HMGB1) protein, which, extracellularly, exerts its actions as a ligand for pattern recognition receptor (PRR) target cell activation. This work studies HMGB1's role in damage recognition and activation of cellular processes. CN (0.025 mg, endotoxin free in 0.050 mL Survanta) was intratracheally instilled into rat airways (n=45). At necropsy 0.5hr to 4 wks later, bronchoalveolar lavage fluid (BAL), lungs and sera were measured (ELISA, cytology) for HMGB1 and 3 cytokines. BALs were also used to activate PRRs in RAW Blue cells, stably transfected lung macrophages expressing the SEAP gene inducible by NF‐kB and AP‐1. HMGB1‐containing BALs induced significant expression of SEAP in the RAW blue cells, highest at 24 hr, which was compared to purified HMGB1 dose‐dependent activation. Histopathology described Inflammation of lung parenchyma and translocation of CN from airways to the mesothelial lining. IL‐10 and IL‐6 in lung related in timing to HMGB1‐receptor complexes (p=0.04). The results show that sterile CN exposure releases lung cell HMGB1, and BAL from this exposure activates raw blue cells at times when HMGB1 is elevated, with related receptors and cytokines.Sponsor: Saint Luke's Hospital Foundation

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