Methods for treating pulmonary disease using inter-alpha inhibitor proteins

Abstract

The invention features methods for treating or preventing pulmonary diseases, including acute respiratory distress syndrome (ARDS) and pneumonia, in a subject in need thereof that involve administering to the subject inter-alpha inhibitor proteins (lalps), including, e.g., inter-alpha inhibitor (lal) and/or pre-alpha inhibitor (Pal).

1 . A method of treating or reducing the likelihood of developing acute respiratory distress syndrome (ARDS) or pneumonia in a subject in need thereof comprising administering to the subject inter-alpha inhibitor proteins (lαlps). 
     
     
         2 . The method of  claim 1 , wherein the lαlps comprise lαl, Pαl, a heavy chain, a light chain, or a combination thereof. 
     
     
         3 . The method of  claim 2 , wherein the lαlps comprise lαl Pαl, and/or bikunin. 
     
     
         4 . The method of  claim 2 , wherein the heavy chain is selected from the group consisting of H1, H2, H3, H4, and H5. 
     
     
         5 . The method of  claim 2 , wherein the light chain is bikunin. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the ARDS or the pneumonia is caused by an infection caused by bacteria. 
     
     
         7 . The method of  claim 6 , wherein the bacteria are antibiotic resistant bacteria. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the method extends a treatment period prior to development of sepsis or organ failure in the subject, relative to an untreated subject. 
     
     
         9 . The method of any one of  claims 1  to  8 , wherein the method comprises treating one or more symptoms of the ARDS comprising mild, moderate or severe hypoxemia as determined by Partial Pressure of arterial oxygen/Fraction of inspired oxygen (PaO 2 /FiO 2 ) or positive end-expiratory pressure (PEEP), bilateral opacities, respiratory failure, shortness of breath, labored breathing, cough, fever, increased heart rate, low blood pressure, confusion, extreme tiredness, rapid breathing, organ failure, chest pain, bluish coloring of nails or lips, an change in the level of one or more inflammatory markers, or need for mechanical ventilation. 
     
     
         10 . The method of  claim 9 , wherein the one or more inflammatory markers is selected from the group consisting of TNF-alpha, IL-6, C5a, DAMPs, ERK, NF-κB, IL-10, and a serine protease. 
     
     
         11 . The method of  claim 9  or  10 , wherein the change in the level of one or more inflammatory markers is an increase. 
     
     
         12 . The method of  claim 9  or  10 , wherein the change in the level of one or more inflammatory markers is a decrease. 
     
     
         13 . The method of any one of  claims 1  to  12 , wherein the subject has one or more symptoms of the ARDS comprising shortness of breath, cough, fever, rapid heart rate, low blood pressure, rapid breathing, chest pain, bluish coloring of nails, or bluish coloring of lips. 
     
     
         14 . The method of any one of  claims 1  to  13 , wherein the ARDS comprises acute respiratory failure (ARF). 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the ARDS results from sepsis, pneumonia, ventilation induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, or administration of resuscitation fluid. 
     
     
         16 . The method of  claim 15 , wherein the chemical fumes are selected from the group consisting of smoke, phosgene, chlorine gas, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, ozone. 
     
     
         17 . The method of  claim 15 , wherein the ARDS results from sepsis. 
     
     
         18 . The method of  claim 17 , wherein the sepsis is infectious sepsis or sterile sepsis. 
     
     
         19 . The method of  claim 15 , wherein the resuscitation fluid comprises colloid solutions. 
     
     
         20 . The method of  claim 19 , wherein the colloid solution comprises hydroxyethyl starch solution. 
     
     
         21 . The method of  claim 20 , wherein the colloid solution comprises albumin. 
     
     
         22 . The method of  claim 15 , wherein the trauma is acidosis. 
     
     
         23 . The method of any one of  claims 1  to  8 , wherein the method comprises treating one or more symptoms of the pneumonia comprising symptoms included in the CRB-65 test, the CURB-65 test, or the pneumonia severity index (PSI), cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation. 
     
     
         24 . The method of any one of  claims 1  to  8 , and  23 , wherein the subject has one or more symptoms of the pneumonia comprising cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation. 
     
     
         25 . The method of any one of  claims 1  to  8 ,  23 , and  24 , wherein the pneumonia comprises hospital-acquired pneumonia (HAP), health care-associated pneumonia (HCAP), nursing home-acquired pneumonia (NHAP), ventilator-associated pneumonia (VAP), or community-acquired pneumonia (CAP). 
     
     
         26 . The method of  claim 25 , wherein the CAP is severe CAP (sCAP). 
     
     
         27 . The method of any one of  claims 1  to  8  and  23  to  26 , wherein the pneumonia results from an infection of lung tissue. 
     
     
         28 . The method of  claim 27 , wherein the infection is a bacterial infection, a viral infection, a fungal infection, a parasite infection, or an infection caused by another type of microorganism. 
     
     
         29 . The method of  claim 28 , wherein the bacterial infection is caused by an  Enterobacteriaceae  species (spp.),  Streptococcus pneumoniae, Staphylococcus aureus, Bacillus anthracis, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bordetella pertussis, Moraxella catarrhalis, Coxiella burnetii, Chlamydophila pneumoniae , a  Legionella  spp., or  Mycoplasma pneumoniae.    
     
     
         30 . The method of  claim 29 , wherein the  Staphylococcus aureus  is methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         31 . The method of  claim 29 , wherein the Legionella species is  Legionella pneumonophila.    
     
     
         32 . The method of  claim 28 , wherein the viral infection is caused by an influenza virus, parainfluenza, swine origin influenza, Respiratory syncytial virus, Human parainfluenza virus, an Adenovirus, a Metapneumovirus, Severe acute respiratory syndrome virus, herpes simplex virus (HSV), Varicella-zoster virus (VZV), measles virus, Rubella virus, Cytomegalovirus (CMV), smallpox virus, dengue virus, rhinovirus, bocavirus, or Middle East respiratory syndrome virus. 
     
     
         33 . The method of  claim 32 , wherein the influenza virus is an influenza virus A or an influenza virus B. 
     
     
         34 . The method of  claim 28 , wherein the fungal infection is caused by  Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Pneumocystis jirovecii, Blastomyces dermatitidis, Sporothrix schenckii, Cryptococcus neoformans, Cryptococcus gattii, Paracoccidioides brasiliensis , a  Candida  spp., an  Aspergillus  spp., or a  Mucor  spp. 
     
     
         35 . The method of any one of  claims 9 - 13 ,  23 , and  24 , wherein the symptoms begin within 2 to 72 hours after a lung insult. 
     
     
         36 . The method of  claim 35 , wherein the lung insult is or is caused by sepsis, pneumonia, ventilation-induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, lung transplant, a large volume of fluid used during post-trauma resuscitation, or infection of lung tissue. 
     
     
         37 . The method of  claim 36 , wherein the lung insult is or is caused by sepsis. 
     
     
         38 . The method of  claim 37 , wherein the sepsis is infectious sepsis or sterile sepsis. 
     
     
         39 . The method of  claim 36 , wherein the chemical fumes are selected from the group consisting of smoke, phosgene, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, ozone or chlorine gas. 
     
     
         40 . The method of any one of  claims 1  to  39 , wherein the method comprises reducing inflammation and/or promoting repair in lung tissue. 
     
     
         41 . The method of any one of  claims 1  to  40 , wherein the method comprises reducing fluid in lung tissue. 
     
     
         42 . The method of  claim 41 , wherein the lung tissue is alveolar lung tissue. 
     
     
         43 . The method of any one of  claims 1  to  42 , wherein the method comprises administering lαlps to the subject prior to development of sepsis in the subject. 
     
     
         44 . The method of any one of  claims 1  to  43 , wherein the method comprises administering lαlps to the subject prior to organ failure in the subject. 
     
     
         45 . The method of any one of  claims 1  to  44 , wherein the method comprises measuring the levels of lαlps in a biological sample derived from the subject prior to administration of the lαlps. 
     
     
         46 . The method of  claim 45 , wherein the method comprises measuring the levels of lαl, Pαl, a heavy chain, a light chain, or a combination thereof. 
     
     
         47 . The method of  claim 46 , wherein the method comprises measuring the levels of lαl and/or Pαl. 
     
     
         48 . The method of any one of  claims 1 - 47 , wherein the method comprises measuring the levels of histones or histone/lαl/Pαl complexes in a biological sample derived from the subject. 
     
     
         49 . The method of any one of  claims 1  to  48 , wherein the subject exhibits decreased levels of lαl and/or Pαl relative to a healthy subject. 
     
     
         50 . The method of any one of  claims 1 - 49 , wherein the subject exhibits increased levels of histones relative to a healthy subject. 
     
     
         51 . The method of any one of  claims 1 - 50 , wherein the subject exhibits increased levels of histone/lαl/Pαl complexes relative to an untreated subject. 
     
     
         52 . The method of any one of  claims 1  to  51 , wherein the method comprises restoring or exceeding the level of lαl and/or Pαl in the lung tissue of the subject to that of a healthy subject. 
     
     
         53 . The method of  claim 49 ,  50 , or  52 , wherein the level of lαl and/or Pαl of a healthy subject is about 300 mg/L to about 1000 mg/L of circulating lαl and/or Pαl. 
     
     
         54 . The method of any one of  claims 1  to  53 , wherein the method comprises administering a single dose or multiple doses of the lαlps sufficient to restore or exceed the level of the lαlps in the lung tissue of the subject. 
     
     
         55 . The method of  claim 54 , wherein the single dose comprises about 1 mg/kg to about 50 mg/kg. 
     
     
         56 . The method of any one of  claims 1  to  55 , wherein the method further comprises measuring the level of one or more biomarkers associated with the ARDS or the pneumonia in a biological sample derived from the subject. 
     
     
         57 . The method of  claim 56 , wherein the one or more biomarkers comprise histone, histone/Pαl complexes, histone/lαl complexes, histone/lαl/Pαl complexes, TNF-α, IL-6, IL-10, IL-1, IL-1ra, IL1B, IL-8, MCP-1, MIP-2, CRP, PCT, cytokine-induced neutrophil chemoattractant/KC, UTI, a complement component, or fragments thereof. 
     
     
         58 . The method of  claim 57 , wherein the complement component is selected from the group consisting of C1, C2, C3, C3a, C3b, C4, C4b, C5, C5a, C5b, C6, C7, C8, C9, membrane attack complex, Factor B, Factor D, MASP-1, and MASP-2. 
     
     
         59 . The method of any one of  claim 45 ,  48 , or  56 - 58 , wherein the biological sample derived from the subject is a blood sample, a urine sample, a sputum sample, or a bronchiolar lavage fluid sample. 
     
     
         60 . The method of  claim 59 , wherein the blood sample is whole blood, serum, plasma, or a combination thereof. 
     
     
         61 . The method of any one of  claims 1  to  60 , wherein the method further comprises administering a second treatment for the ARDS or the pneumonia. 
     
     
         62 . The method of  claim 61 , wherein the second treatment comprises one or more of an antibiotic, an antiviral agent, an antifungal agent, an antiparasitic agent, an anti-inflammatory agent, a bronchodilator, a vasopressor, a sedative, or mechanical ventilation. 
     
     
         63 . The method of any one of  claims 1  to  62 , wherein the method further comprises administering an inhibitor of complement activation. 
     
     
         64 . The method of any one of  claims 1  to  63 , wherein the method comprises neutralization of histones and extracellular histones. 
     
     
         65 . The method of any one of  claims 1  to  64 , wherein the administration of the lαlps inhibits activation of one or more complement components. 
     
     
         66 . The method of  claim 65 , wherein the complement components comprise C1, C2, C3, C3a, C3b, C4, C4b, C5, C5a, C5b, C6, C7, C8, C9, membrane attack complex, Factor B, Factor D, MASP-1, MASP-2, or fragments thereof. 
     
     
         67 . The method of any one of  claims 1  to  66 , wherein the administration of the lαlps reduces the likelihood of death or hospitalization time for the subject. 
     
     
         68 . The method of any one of  claims 1  to  67 , wherein the method comprises administering a composition comprising lαl and/or Pαl. 
     
     
         69 . The method of  claim 68 , wherein the composition comprises a dosage of lαl and/or Pαl of about 1 mg/kg to about 50 mg/kg. 
     
     
         70 . The method of  claim 69 , wherein the composition comprises a dosage of the lαl and/or Pαl proteins of about 5 mg/kg to about 15 mg/kg. 
     
     
         71 . The method of any one of  claims 68  to  70 , wherein the composition is administered to the subject one or more times every 1, 2, 3, 4, 5, 6, 8, 12, or 24 hours, every 1, 2, 3, 4, 5, or 6, days, or every 1, 2, 3, or 4 weeks. 
     
     
         72 . The method of any one of  claims 68  to  71 , wherein the composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         73 . The method of any one of  claims 68  to  72 , wherein the composition is formulated as a solid. 
     
     
         74 . The method of any one of  claims 68  to  73 , wherein the composition is formulated as a liquid. 
     
     
         75 . The method of any one of  claims 68  to  74 , wherein the composition is formulated for inhalation, insufflation, nebulization, or injection, or is formulated for oral, rectal, topical, or intraperitoneal administration. 
     
     
         76 . The method of  claim 75 , wherein the injection is intravenous injection. 
     
     
         77 . The method of any one of  claims 68  to  76 , wherein the composition has a half-life of greater than 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, or 10 hours. 
     
     
         78 . The method of any one of  claims 68  to  77 , wherein the composition further comprises an antibiotic, an antiviral agent, an antifungal agent, an anti-parasitic agent, an anti-inflammatory agent, a vasopressor, a sedative, or a bronchodilator. 
     
     
         79 . The method of  claim 78 , wherein the antibiotic agent comprises amoxicillin, penicillin, doxycycline, clarithromycin, benzylpenicillin, azithromycin, daptomycin, linezolid, levofloxacin, moxifloxacin, gatifloxcin, gentamicin, macrolides, cephalosporins, azithromycin, ciprofloxacin, cefuroxime, amoxillin-potassium clavulanate, erythromycin, sulfamethoxazole-trimethoprim, doxycycline monohydrate, cefepime, ampicillin, cefpodoxime, ceftriaxone, cefazolin, erythromycin ethylsuccinate, meropenem, piperacillin-tazobactam, amikacin, erythromycin stearate, cefepime in dextrose, doxycycline hyclate, ampicillin-sulbactam, ceftazidime, gemifloxacin, gentamicin sulfate, erythromycin lactobionate, imipenem-cilastatin, cefoxitin, cefditoren pivoxil, ertapenem, doxycycline-benzoyl peroxide, ampicillin-sulbactam, meropenem, cefuroxime, cefotetan, or piperacillin-tazobactam. 
     
     
         80 . The method of  claim 78 , wherein the antiviral agent comprises zanamivir, oseltamivir, permivir, ribavirin, acyclovir, ganciclovir, foscarnet, or cidofovir. 
     
     
         81 . The method of  claim 78 , wherein the antifungal agent comprises amphotericin, caspofungin, voriconazole, itraconazole, posaconazole, fluconazole, or flucytosine. 
     
     
         82 . The method of  claim 78 , wherein the antiparasitic agent comprises nitazoxanide, melarsoprol, eflornithine, metronidazole, tinidazole, miltefosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, albendazole, praziquantel, or rifampin. 
     
     
         83 . The method of  claim 78 , wherein the anti-inflammatory agent comprises a corticosteroid, a statin, a steroid, a nonsteroidal anti-inflammatory drug, or a glucocorticoid. 
     
     
         84 . The method of  claim 78 , wherein the bronchodilator comprises a beta 2 agonist, a xanthine, ipratropium, oxitropium, a muscarinic receptor antagonist, ipratropium, oxitropium, theophylline, theobromine, caffeine, salbutamol, isoproterenol, albuterol, levalburerol, pirbuterol, metaproterenol, terbutaline, salmeterol, or formoterol. 
     
     
         85 . The method of  claim 78 , wherein the vasopressor comprises epinephrine, isoproterenol, phenylephrine, norepinephrine, dobutamine, ephedrine, or droxidopa. 
     
     
         86 . The method of  claim 78 , wherein the sedative comprises propofol, diprivan, morphine, fentanyl, midazolam, lorazepam, precede, infumorph, dexmedetomidine, or alfentanil. 
     
     
         87 . The method of any one of  claims 1  to  86 , wherein the composition further comprises an inhibitor of complement activation. 
     
     
         88 . The method of  claim 87 , wherein the composition inhibits activation of one or more complement components. 
     
     
         89 . The method of  claim 88 , wherein the complement components comprise C1, C2, C3, C4, C5, or fragments thereof. 
     
     
         90 . The method of any one of  claims 1  to  89 , wherein the subject is a mammal. 
     
     
         91 . The method of  claim 90 , wherein the mammal is human. 
     
     
         92 . The method of  claim 91 , wherein the human is an infant, a child, or an adult. 
     
     
         93 . The method of  claim 90 , wherein the mammal is a horse, a dog, a cat, a rabbit, or a pig. 
     
     
         94 . The method of any one of  claims 1  to  93 , wherein the subject has the ARDS or the pneumonia. 
     
     
         95 . The method of any one of  claims 1  to  94 , wherein the subject is not hospitalized. 
     
     
         96 . The method of any one of  claims 1  to  94 , wherein the subject is hospitalized. 
     
     
         97 . The method of  claim 96 , wherein the subject is in an intensive care unit. 
     
     
         98 . The method of any one of  claims 1  to  97 , wherein the subject requires ventilator-assisted breathing. 
     
     
         99 . The method of  claim 98 , wherein the ventilator-assisted breathing is mechanical ventilator-assisted breathing. 
     
     
         100 . The method of  claim 99 , wherein the mechanical ventilator-assisted breathing is invasive mechanical ventilator-assisted breathing. 
     
     
         101 . The method of  claim 99 , wherein the mechanical ventilator-assisted breathing is non-invasive mechanical ventilator-assisted breathing. 
     
     
         102 . The method of  claim 99 , wherein the mechanical ventilator-assisted breathing is pressure-limited or volume-limited. 
     
     
         103 . The method of any one of  claims 1  to  102 , wherein the subject has one or more organ failures. 
     
     
         104 . The method of  claim 103 , wherein the subject has two or more organ failures. 
     
     
         105 . The method of  claim 104 , wherein the subject has failures of the liver failure, kidney, intestine, heart, or brain. 
     
     
         106 . The method of any one of  claims 103  to  105 , wherein the subject has respiratory failure. 
     
     
         107 . The method of any one of  claims 1  to  106 , wherein the subject is identified as being in need of treatment using one or more of the following: chest imaging, arterial blood gas level, partial pressure of oxygen (PaO 2 ) levels, partial pressure of carbon dioxide (PaCO 2 ) levels, blood pH, pathogen specific test, or sputum evaluation. 
     
     
         108 . The method of  claim 107 , wherein the chest imaging is chest X-ray. 
     
     
         109 . The method of any one of  claims 1  to  108 , wherein the subject is identified as having mild, moderate or severe hypoxemia as determined by PaO 2 /FiO 2  or positive end-expiratory pressure (PEEP). 
     
     
         110 . The method of any one of  claims 1  to  109 , wherein the subject is identified as having bilateral opacities consistent with edema. 
     
     
         111 . The method of any one of  claims 1  to  110 , wherein the subject is identified as having confusion, blood urea nitrogen being equal to one more than 20 mg/dL, respiratory rate being equal to or greater than 30 breaths per minute, systolic blood pressure being less than 90 mm Hg, diastolic blood pressure being equal to or less than 60 mm Hg, or is 65 or older. 
     
     
         112 . The method of any one of  claims 1  to  111 , wherein the subject is identified as being a nursing home resident; having neoplastic disease; having a history of liver, heart, cerebrovascular, or renal disease; being in a state of altered mental state; having a respiratory rate greater than or equal to 30 breaths per minute; having a systolic blood pressure above 90 mmHg, having a temperature above 35° C. or greater than or equal to 40° C.; having a pulse greater than or equal to 125/min; arterial pH less than 7.35; having a blood urea nitrogen greater than or equal to 30 ng/dL, sodium levels being greater than 130 mmol/L; having glucose levels greater than or equal to 250 mg/dl or greater than 13.8 mmol/liter); having hematocrit values being less than 30%; having a partial pressure of oxygen less than 60 mm Hg; or by the presence of pleural effusion on X-ray. 
     
     
         113 . The method of any one of  claims 1  to  112 , wherein the administration of the lαlps reduces the physiological response to inflammatory mediators such as cytokines, chemokines, complement, or histones. 
     
     
         114 . The method of any one of  claims 1  to  113 , wherein the subject has undergone a lung transplant. 
     
     
         115 . The method of any one of  claims 1  to  114 , wherein the subject is scheduled to undergo a lung transplant. 
     
     
         116 . The method of any one of  claims 1  to  115 , wherein the method comprises administering the lαlps to the subject at least 10, 15, 20, 30, 60, or 120 minutes after a lung insult. 
     
     
         117 . The method of  claim 116 , wherein the lung insult occurs as a result of radiation treatment, chemotherapy, or exposure to high altitude, swimming, or diving. 
     
     
         118 . The method of any one of  claims 1  to  115 , wherein the method comprises administering the lαlps to the subject at least 10, 15, 20, 30, 60, or 120 minutes before a lung insult. 
     
     
         119 . The method of  claim 118 , wherein the lung insult occurs as a result of surgery. 
     
     
         120 . The method of any one of  claims 3  or  6  to  119 , wherein the lαlps are administered at physiological proportions. 
     
     
         121 . The method of any one of  claims 3  or  6  to  120 , wherein the lαlps are at about 80% to about 100% purity. 
     
     
         122 . The method of  claim 1 , wherein the method extends a treatment period prior to development of sepsis or organ failure in the subject, relative to an untreated subject. 
     
     
         123 . The method of  claim 1 , wherein the method comprises treating one or more symptoms of the ARDS comprising mild, moderate or severe hypoxemia as determined by Partial Pressure of arterial oxygen/Fraction of inspired oxygen (PaO 2 /FiO 2 ) or positive end-expiratory pressure (PEEP), bilateral opacities, respiratory failure, shortness of breath, labored breathing, cough, fever, increased heart rate, low blood pressure, confusion, extreme tiredness, rapid breathing, organ failure, chest pain, bluish coloring of nails or lips, an change in the level of one or more inflammatory markers, or need for mechanical ventilation. 
     
     
         124 . The method of  claim 123 , wherein the one or more inflammatory markers is selected from the group consisting of TNF-alpha, IL-6, C5a, DAMPs, ERK, NF-κB, IL-10, and a serine protease. 
     
     
         125 . The method of  claim 123 , wherein the change in the level of one or more inflammatory markers is an increase. 
     
     
         126 . The method of  claim 124 , wherein the change in the level of one or more inflammatory markers is an increase. 
     
     
         127 . The method of  claim 123 , wherein the change in the level of one or more inflammatory markers is a decrease. 
     
     
         128 . The method of  claim 124 , wherein the change in the level of one or more inflammatory markers is a decrease. 
     
     
         129 . The method of  claim 1 , wherein the subject has one or more symptoms of the ARDS comprising shortness of breath, cough, fever, rapid heart rate, low blood pressure, rapid breathing, chest pain, bluish coloring of nails, or bluish coloring of lips. 
     
     
         130 . The method of  claim 1 , wherein the ARDS comprises acute respiratory failure (ARF). 
     
     
         131 . The method of  claim 1 , wherein the ARDS results from sepsis, pneumonia, ventilation induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, or administration of resuscitation fluid. 
     
     
         132 . The method of  claim 131 , wherein the chemical fumes are selected from the group consisting of smoke, phosgene, chlorine gas, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, ozone. 
     
     
         133 . The method of  claim 131 , wherein the ARDS results from sepsis. 
     
     
         134 . The method of  claim 133 , wherein the sepsis is infectious sepsis or sterile sepsis. 
     
     
         135 . The method of  claim 131 , wherein the resuscitation fluid comprises colloid solutions. 
     
     
         136 . The method of  claim 135 , wherein the colloid solution comprises hydroxyethyl starch solution. 
     
     
         137 . The method of  claim 136 , wherein the colloid solution comprises albumin. 
     
     
         138 . The method of  claim 131 , wherein the trauma is acidosis. 
     
     
         139 . The method of  claim 1 , wherein the method comprises treating one or more symptoms of the pneumonia comprising symptoms included in the CRB-65 test, the CURB-65 test, or the pneumonia severity index (PSI), cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation. 
     
     
         140 . The method of  claim 1 , wherein the subject has one or more symptoms of the pneumonia comprising cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation. 
     
     
         141 . The method of  claim 1 , wherein the pneumonia comprises hospital-acquired pneumonia (HAP), health care-associated pneumonia (HCAP), nursing home-acquired pneumonia (NHAP), ventilator-associated pneumonia (VAP), or community-acquired pneumonia (CAP). 
     
     
         142 . The method of  claim 141 , wherein the CAP is severe CAP (sCAP). 
     
     
         143 . The method of  claim 1 , wherein the pneumonia results from an infection of lung tissue. 
     
     
         144 . The method of  claim 143 , wherein the infection is a bacterial infection, a viral infection, a fungal infection, a parasite infection, or an infection caused by another type of microorganism. 
     
     
         145 . The method of  claim 144 , wherein the bacterial infection is caused by an  Enterobacteriaceae  species (spp.),  Streptococcus pneumoniae, Staphylococcus aureus, Bacillus anthracis, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bordetella pertussis, Moraxella catarrhalis, Coxiella burnetii, Chlamydophila pneumoniae , a  Legionella  spp., or  Mycoplasma pneumoniae.    
     
     
         146 . The method of  claim 145 , wherein the  Staphylococcus aureus  is methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         147 . The method of  claim 145 , wherein the  Legionella  species is  Legionella  pneumonophila. 
     
     
         148 . The method of  claim 144 , wherein the viral infection is caused by an influenza virus, parainfluenza, swine origin influenza, Respiratory syncytial virus, Human parainfluenza virus, an Adenovirus, a Metapneumovirus, Severe acute respiratory syndrome virus, herpes simplex virus (HSV), Varicella-zoster virus (VZV), measles virus, Rubella virus, Cytomegalovirus (CMV), smallpox virus, dengue virus, rhinovirus, bocavirus, or Middle East respiratory syndrome virus. 
     
     
         149 . The method of  claim 148 , wherein the influenza virus is an influenza virus A or an influenza virus B. 
     
     
         150 . The method of  claim 144 , wherein the fungal infection is caused by  Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Pneumocystis jirovecii, Blastomyces dermatitidis, Sporothrix schenckii, Cryptococcus neoformans, Cryptococcus gattii, Paracoccidioides brasiliensis , a  Candida  spp., an  Aspergillus  spp., or a  Mucor  spp. 
     
     
         151 . The method of  claim 9 , wherein the symptoms begin within 2 to 72 hours after a lung insult. 
     
     
         152 . The method of  claim 151 , wherein the lung insult is or is caused by sepsis, pneumonia, ventilation-induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, lung transplant, a large volume of fluid used during post-trauma resuscitation, or infection of lung tissue. 
     
     
         153 . The method of  claim 152 , wherein the lung insult is or is caused by sepsis. 
     
     
         154 . The method of  claim 153 , wherein the sepsis is infectious sepsis or sterile sepsis. 
     
     
         155 . The method of  claim 152 , wherein the chemical fumes are selected from the group consisting of smoke, phosgene, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, ozone or chlorine gas. 
     
     
         156 . The method of  claim 1 , wherein the method comprises reducing inflammation and/or promoting repair in lung tissue. 
     
     
         157 . The method of  claim 1 , wherein the method comprises reducing fluid in lung tissue. 
     
     
         158 . The method of  claim 157 , wherein the lung tissue is alveolar lung tissue. 
     
     
         159 . The method of  claim 1 , wherein the method comprises administering lαlps to the subject prior to development of sepsis in the subject. 
     
     
         160 . The method of  claim 1 , wherein the method comprises administering lαlps to the subject prior to organ failure in the subject. 
     
     
         161 . The method of  claim 1 , wherein the method comprises measuring the levels of lαlps in a biological sample derived from the subject prior to administration of the lαlps. 
     
     
         162 . The method of  claim 161 , wherein the method comprises measuring the levels of lαl, Pαl, a heavy chain, a light chain, or a combination thereof. 
     
     
         163 . The method of  claim 162 , wherein the method comprises measuring the levels of lαl and/or Pαl. 
     
     
         164 . The method of  claim 1 , wherein the method comprises measuring the levels of histones or histone/lαl/Pαl complexes in a biological sample derived from the subject. 
     
     
         165 . The method of  claim 1 , wherein the subject exhibits decreased levels of lαl and/or Pαl relative to a healthy subject. 
     
     
         166 . The method of  claim 1 , wherein the subject exhibits increased levels of histones relative to a healthy subject. 
     
     
         167 . The method of  claim 1 , wherein the subject exhibits increased levels of histone/lαl/Pαl complexes relative to an untreated subject. 
     
     
         168 . The method of  claim 1 , wherein the method comprises restoring or exceeding the level of lαl and/or Pαl in the lung tissue of the subject to that of a healthy subject. 
     
     
         169 . The method of  claim 165 , wherein the level of lαl and/or Pαl of a healthy subject is about 300 mg/L to about 1000 mg/L of circulating lαl and/or Pαl. 
     
     
         170 . The method of  claim 166 , wherein the level of lαl and/or Pαl of a healthy subject is about 300 mg/L to about 1000 mg/L of circulating lαl and/or Pαl. 
     
     
         171 . The method of  claim 168 , wherein the level of lαl and/or Pαl of a healthy subject is about 300 mg/L to about 1000 mg/L of circulating lαl and/or Pαl. 
     
     
         172 . The method of  claim 1 , wherein the method comprises administering a single dose or multiple doses of the lαlps sufficient to restore or exceed the level of the lαlps in the lung tissue of the subject. 
     
     
         173 . The method of  claim 172 , wherein the single dose comprises about 1 mg/kg to about 50 mg/kg. 
     
     
         174 . The method of  claim 1 , wherein the method further comprises measuring the level of one or more biomarkers associated with the ARDS or the pneumonia in a biological sample derived from the subject. 
     
     
         175 . The method of  claim 174 , wherein the one or more biomarkers comprise histone, histone/Pαl complexes, histone/lαl complexes, histone/lαl/Pαl complexes, TNF-α, IL-6, IL-10, IL-1, IL-1ra, IL1B, IL-8, MCP-1, MIP-2, CRP, PCT, cytokine-induced neutrophil chemoattractant/KC, UTI, a complement component, or fragments thereof. 
     
     
         176 . The method of  claim 175 , wherein the complement component is selected from the group consisting of C1, C2, C3, C3a, C3b, C4, C4b, C5, C5a, C5b, C6, C7, C8, C9, membrane attack complex, Factor B, Factor D, MASP-1, and MASP-2. 
     
     
         177 . The method of  claim 161 , wherein the biological sample derived from the subject is a blood sample, a urine sample, a sputum sample, or a bronchiolar lavage fluid sample. 
     
     
         178 . The method of  claim 164 , wherein the biological sample derived from the subject is a blood sample, a urine sample, a sputum sample, or a bronchiolar lavage fluid sample. 
     
     
         179 . The method of  claim 174 , wherein the biological sample derived from the subject is a blood sample, a urine sample, a sputum sample, or a bronchiolar lavage fluid sample. 
     
     
         180 . The method of  claim 177 , wherein the blood sample is whole blood, serum, plasma, or a combination thereof. 
     
     
         181 . The method of  claim 178 , wherein the blood sample is whole blood, serum, plasma, or a combination thereof. 
     
     
         182 . The method of  claim 179 , wherein the blood sample is whole blood, serum, plasma, or a combination thereof. 
     
     
         183 . The method of  claim 1 , wherein the method further comprises administering a second treatment for the ARDS or the pneumonia. 
     
     
         184 . The method of  claim 183 , wherein the second treatment comprises one or more of an antibiotic, an antiviral agent, an antifungal agent, an antiparasitic agent, an anti-inflammatory agent, a bronchodilator, a vasopressor, a sedative, or mechanical ventilation. 
     
     
         185 . The method of  claim 1 , wherein the method further comprises administering an inhibitor of complement activation. 
     
     
         186 . The method of  claim 1 , wherein the method comprises neutralization of histones and extracellular histones. 
     
     
         187 . The method of  claim 1 , wherein the administration of the lαlps inhibits activation of one or more complement components. 
     
     
         188 . The method of  claim 187 , wherein the complement components comprise C1, C2, C3, C3a, C3b, C4, C4b, C5, C5a, C5b, C6, C7, C8, C9, membrane attack complex, Factor B, Factor D, MASP-1, MASP-2, or fragments thereof. 
     
     
         189 . The method of  claim 1 , wherein the administration of the lαlps reduces the likelihood of death or hospitalization time for the subject. 
     
     
         190 . The method of  claim 1 , wherein the method comprises administering a composition comprising lαl and/or Pαl. 
     
     
         191 . The method of  claim 190 , wherein the composition comprises a dosage of lαl and/or Pαl of about 1 mg/kg to about 50 mg/kg. 
     
     
         192 . The method of  claim 191 , wherein the composition comprises a dosage of the lαl and/or Pαl proteins of about 5 mg/kg to about 15 mg/kg. 
     
     
         193 . The method of  claim 190 , wherein the composition is administered to the subject one or more times every 1, 2, 3, 4, 5, 6, 8, 12, or 24 hours, every 1, 2, 3, 4, 5, or 6, days, or every 1, 2, 3, or 4 weeks. 
     
     
         194 . The method of  claim 190 , wherein the composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         195 . The method of  claim 190 , wherein the composition is formulated as a solid. 
     
     
         196 . The method of  claim 190 , wherein the composition is formulated as a liquid. 
     
     
         197 . The method of  claim 190 , wherein the composition is formulated for inhalation, insufflation, nebulization, or injection, or is formulated for oral, rectal, topical, or intraperitoneal administration. 
     
     
         198 . The method of  claim 197 , wherein the injection is intravenous injection. 
     
     
         199 . The method of  claim 190 , wherein the composition has a half-life of greater than 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, or 10 hours. 
     
     
         200 . The method of  claim 190 , wherein the composition further comprises an antibiotic, an antiviral agent, an antifungal agent, an anti-parasitic agent, an anti-inflammatory agent, a vasopressor, a sedative, or a bronchodilator. 
     
     
         201 . The method of  claim 200 , wherein the antibiotic agent comprises amoxicillin, penicillin, doxycycline, clarithromycin, benzylpenicillin, azithromycin, daptomycin, linezolid, levofloxacin, moxifloxacin, gatifloxcin, gentamicin, macrolides, cephalosporins, azithromycin, ciprofloxacin, cefuroxime, amoxillin-potassium clavulanate, erythromycin, sulfamethoxazole-trimethoprim, doxycycline monohydrate, cefepime, ampicillin, cefpodoxime, ceftriaxone, cefazolin, erythromycin ethylsuccinate, meropenem, piperacillin-tazobactam, amikacin, erythromycin stearate, cefepime in dextrose, doxycycline hyclate, ampicillin-sulbactam, ceftazidime, gemifloxacin, gentamicin sulfate, erythromycin lactobionate, imipenem-cilastatin, cefoxitin, cefditoren pivoxil, ertapenem, doxycycline-benzoyl peroxide, ampicillin-sulbactam, meropenem, cefuroxime, cefotetan, or piperacillin-tazobactam. 
     
     
         202 . The method of  claim 200 , wherein the antiviral agent comprises zanamivir, oseltamivir, permivir, ribavirin, acyclovir, ganciclovir, foscarnet, or cidofovir. 
     
     
         203 . The method of  claim 200 , wherein the antifungal agent comprises amphotericin, caspofungin, voriconazole, itraconazole, posaconazole, fluconazole, or flucytosine. 
     
     
         204 . The method of  claim 200 , wherein the antiparasitic agent comprises nitazoxanide, melarsoprol, eflornithine, metronidazole, tinidazole, miltefosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, albendazole, praziquantel, or rifampin. 
     
     
         205 . The method of  claim 200 , wherein the anti-inflammatory agent comprises a corticosteroid, a statin, a steroid, a nonsteroidal anti-inflammatory drug, or a glucocorticoid. 
     
     
         206 . The method of  claim 200 , wherein the bronchodilator comprises a beta 2 agonist, a xanthine, ipratropium, oxitropium, a muscarinic receptor antagonist, ipratropium, oxitropium, theophylline, theobromine, caffeine, salbutamol, isoproterenol, albuterol, levalburerol, pirbuterol, metaproterenol, terbutaline, salmeterol, or formoterol. 
     
     
         207 . The method of  claim 200 , wherein the vasopressor comprises epinephrine, isoproterenol, phenylephrine, norepinephrine, dobutamine, ephedrine, or droxidopa. 
     
     
         208 . The method of  claim 200 , wherein the sedative comprises propofol, diprivan, morphine, fentanyl, midazolam, lorazepam, precede, infumorph, dexmedetomidine, or alfentanil. 
     
     
         209 . The method of  claim 1 , wherein the composition further comprises an inhibitor of complement activation. 
     
     
         210 . The method of  claim 209 , wherein the composition inhibits activation of one or more complement components. 
     
     
         211 . The method of  claim 210 , wherein the complement components comprise C1, C2, C3, C4, C5, or fragments thereof. 
     
     
         212 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         213 . The method of  claim 212 , wherein the mammal is human. 
     
     
         214 . The method of  claim 213 , wherein the human is an infant, a child, or an adult. 
     
     
         215 . The method of  claim 212 , wherein the mammal is a horse, a dog, a cat, a rabbit, or a pig. 
     
     
         216 . The method of  claim 1 , wherein the subject has the ARDS or the pneumonia. 
     
     
         217 . The method of  claim 1 , wherein the subject is not hospitalized. 
     
     
         218 . The method of  claim 1 , wherein the subject is hospitalized. 
     
     
         219 . The method of  claim 218 , wherein the subject is in an intensive care unit. 
     
     
         220 . The method of  claim 1 , wherein the subject requires ventilator-assisted breathing. 
     
     
         221 . The method of  claim 220 , wherein the ventilator-assisted breathing is mechanical ventilator-assisted breathing. 
     
     
         222 . The method of  claim 221 , wherein the mechanical ventilator-assisted breathing is invasive mechanical ventilator-assisted breathing. 
     
     
         223 . The method of  claim 221 , wherein the mechanical ventilator-assisted breathing is non-invasive mechanical ventilator-assisted breathing. 
     
     
         224 . The method of  claim 221 , wherein the mechanical ventilator-assisted breathing is pressure-limited or volume-limited. 
     
     
         225 . The method of  claim 1 , wherein the subject has one or more organ failures. 
     
     
         226 . The method of  claim 225 , wherein the subject has two or more organ failures. 
     
     
         227 . The method of  claim 226 , wherein the subject has failures of the liver failure, kidney, intestine, heart, or brain. 
     
     
         228 . The method of  claim 225 , wherein the subject has respiratory failure. 
     
     
         229 . The method of  claim 1 , wherein the subject is identified as being in need of treatment using one or more of the following: chest imaging, arterial blood gas level, partial pressure of oxygen (PaO 2 ) levels, partial pressure of carbon dioxide (PaCO 2 ) levels, blood pH, pathogen specific test, or sputum evaluation. 
     
     
         230 . The method of  claim 229 , wherein the chest imaging is chest X-ray. 
     
     
         231 . The method of  claim 1 , wherein the subject is identified as having mild, moderate or severe hypoxemia as determined by PaO 2 /FiO 2  or positive end-expiratory pressure (PEEP). 
     
     
         232 . The method of  claim 1 , wherein the subject is identified as having bilateral opacities consistent with edema. 
     
     
         233 . The method of  claim 1 , wherein the subject is identified as having confusion, blood urea nitrogen being equal to one more than 20 mg/dL, respiratory rate being equal to or greater than 30 breaths per minute, systolic blood pressure being less than 90 mm Hg, diastolic blood pressure being equal to or less than 60 mm Hg, or is 65 or older. 
     
     
         234 . The method of  claim 1 , wherein the subject is identified as being a nursing home resident; having neoplastic disease; having a history of liver, heart, cerebrovascular, or renal disease; being in a state of altered mental state; having a respiratory rate greater than or equal to 30 breaths per minute; having a systolic blood pressure above 90 mmHg, having a temperature above 35° C. or greater than or equal to 40° C.; having a pulse greater than or equal to 125/min; arterial pH less than 7.35; having a blood urea nitrogen greater than or equal to 30 ng/dL, sodium levels being greater than 130 mmol/L; having glucose levels greater than or equal to 250 mg/dl or greater than 13.8 mmol/liter); having hematocrit values being less than 30%; having a partial pressure of oxygen less than 60 mm Hg; or by the presence of pleural effusion on X-ray. 
     
     
         235 . The method of  claim 1 , wherein the administration of the lαlps reduces the physiological response to inflammatory mediators such as cytokines, chemokines, complement, or histones. 
     
     
         236 . The method of  claim 1 , wherein the subject has undergone a lung transplant. 
     
     
         237 . The method of  claim 1 , wherein the subject is scheduled to undergo a lung transplant. 
     
     
         238 . The method of  claim 1 , wherein the method comprises administering the lαlps to the subject at least 10, 15, 20, 30, 60, or 120 minutes after a lung insult. 
     
     
         239 . The method of  claim 238 , wherein the lung insult occurs as a result of radiation treatment, chemotherapy, or exposure to high altitude, swimming, or diving. 
     
     
         240 . The method of  claim 1 , wherein the method comprises administering the lαlps to the subject at least 10, 15, 20, 30, 60, or 120 minutes before a lung insult. 
     
     
         241 . The method of  claim 240 , wherein the lung insult occurs as a result of surgery. 
     
     
         242 . The method of  claim 3 , wherein the lαlps are administered at physiological proportions. 
     
     
         243 . The method of  claim 3 , wherein the lαlps are at about 80% to about 100% purity. 
     
     
         244 . The method of  claim 242 , wherein the lαlps are at about 80% to about 100% purity.